Medicinal inhalation devices and components thereof

ABSTRACT

A medicinal inhalation device having a non-metal coating coated on at least a portion thereof, and onto which non-metal coating an at least partially fluorinated compound is then covalently bonded.

FIELD OF THE INVENTION

The present invention relates to medicinal inhalation devices andcomponents for such devices as well as methods of making such devicesand components.

BACKGROUND OF THE INVENTION

Medicinal inhalation devices, including pressurized inhalers, such asmetered dose pressurized inhalers (MDIs), and dry powder inhalers(DPIs), are widely used for delivering medicaments.

Medicinal inhalation devices typically comprise a plurality of hardwarecomponents, (which in the case of a MDI can include for example gasketseals; metered dose valves (including their individual components, suchas ferrules, valve bodies, valve stems, tanks, springs retaining cupsand seals); containers; and actuators) as well as a number of internalsurfaces which may be in contact with the medicinal formulation duringstorage or come in contact with the medicinal formulation duringdelivery. Often a desirable material for a particular component is foundto be unsuitable in regard to its surface properties, e.g. surfaceenergy, and/or its interaction with the medicinal formulation. Forexample, the relatively high surface energy of materials typically usedin MDIs, e.g. acetal polymer for valve stems, or deep drawn stainlesssteels or aluminum for containers, can cause medicament particles insuspension formulations to adhere irreversibly to the surfaces ofcorresponding component(s), which has a consequent impact on theuniformity of medicinal delivery. Similar effects are also observed forDPIs. Other examples of potentially undesirable interactions between acomponent and the medicinal formulation may include enhanced medicamentdegradation; adsorption of medicament or permeation of a formulationconstituent or extraction of chemicals from plastic materials. For DPIsoften permeation and adsorption of ambient water pose issues. Also theuse of materials having relatively high surface energy for certaincomponents (e.g. metered dose valves and/or individual componentsthereof), may have undesirable effects for the operation of movablecomponents of a medicinal inhalation device.

Various coatings have been proposed for particular components orsurfaces of metered dose inhalers, see e.g. EP 642 992, WO 96/32099, WO96/32150-1, WO 96/32345, WO 99/42154, WO 02/47829, WO03/024623; WO02/30498, WO 01/64273; WO 91/64274-5; WO 01/64524; and WO 03/006181.

SUMMARY OF THE INVENTION

Although a number of different coatings have been proposed, there is anongoing need for medicinal inhalation devices and components thereofhaving desirable surface properties (e.g. low surface energy) inconjunction with desirable structural integrity (e.g. adhesion,durability, robustness and/or resistance to degradation over thelifetime of the device) of a coating system provided on said devices andcomponents as well as methods of providing such medicinal inhalationdevices and components.

In aspects of the present invention there is provided a method of makinga medicinal inhalation device or a component of a medicinal inhalationdevice comprising:

-   -   a) forming a non-metal coating on at least a portion of a        surface of the medicinal inhalation device or a component of a        medicinal inhalation device, respectively, said coating having        at least one functional group;    -   b) applying to at least a portion of a surface of the non-metal        coating a composition comprising an at least partially        fluorinated compound comprising at least one functional group;        and    -   c) allowing at least one functional group of the at least        partially fluorinated compound to react with at least one        functional group of the non-metal coating to form a covalent        bond.

Additional aspects of the present invention include: devices andcomponents made in accordance with aforesaid methods; a medicinalinhalation device or a component of a medicinal inhalation devicecomprising a non-metal coating on at least a portion of a surface of thedevice or the component, respectively, and a fluorine-containing coatingbonded to the non-metal coating wherein the fluorine-containing coatingcomprises an at least partially fluorinated compound comprising at leastone functional group which shares at least one covalent bond with thenon-metal coating.

The application of such a non-metal coating covalently bonded to an atleast partially fluorinated compound as described herein providesdesirable surface properties (e.g. low surface energy) in conjunctionwith desirable structural integrity of the system provided on surfacesof said devices and components.

Such desirable structural integrity can be further enhanced throughcertain favorable embodiments in which the non-metal coating issubstantially free (more favorably free) of fluorine. Alternatively oradditionally, structural integrity can be further enhanced in certainfavorable embodiments in which the non-metal coating is covalentlybonded to the at least a portion of a surface of the device orcomponent. Alternatively or additionally, in other certain favorableembodiments, structural integrity as well as impermeabilitycharacteristics can be further facilitated through a non-metal coatingthat is plasma deposited under ion bombardment conditions.

Further aspects of the present invention include: a medicinal inhalationdevice or component of a medicinal inhalation device comprising anon-metal coating plasma deposited on at least a portion of a surface ofthe device or component, respectively, said coating being plasmadeposited under ion bombardment conditions and being substantially free(or more favorably) free of fluorine. Other aspects of the presentinvention include: a medicinal inhalation device or a component of amedicinal inhalation device comprising a diamond-like glass coating onat least a portion of a surface of the device or component,respectively. Such medicinal inhalation devices and components (inparticular medicinal inhalation devices comprising such components) showsurprisingly desirable surface properties in conjunction with veryfavorable structural integrity.

Dependent claims define further embodiments of the invention.

The invention, in its various combinations, either in method orapparatus form, may also be characterized by the following listing ofitems:

1. A method of making a medicinal inhalation device comprising:

-   -   a) forming a non-metal coating on at least a portion of a        surface of the device, said coating having at least one        functional group;    -   b) applying to at least a portion of a surface of the non-metal        coating a composition comprising an at least partially        fluorinated compound comprising at least one functional group;        and    -   c) allowing at least one functional group of the at least        partially fluorinated compound to react with at least one        functional group of the non-metal coating to form a covalent        bond.        2. A method of making a component of a medicinal inhalation        device comprising:    -   a) forming a non-metal coating on at least a portion of a        surface of the component, said coating having at least one        functional group;    -   b) applying to at least a portion of a surface of the non-metal        coating a composition comprising an at least partially        fluorinated compound comprising at least one functional group;        and    -   c) allowing at least one functional group of the at least        partially fluorinated compound to react with at least one        functional group of the non-metal coating to form a covalent        bond.        3. A method according to item 1 or item 2, wherein said at least        one functional group of the non-metal coating has an active        hydrogen.        4. A method according to item 3, wherein said at least one        functional group of the non-metal coating having an active        hydrogen is selected from the group consisting of a hydroxyl        group (—OH), a thiol group (—SH), an amine group (—NH— or —NH₂),        a carboxyl group (—COOH) or an amide group (—CONH— or —CONH₂).        5. A method according to item 4, wherein said at least one        functional group of the non-metal coating having an active        hydrogen is selected from the group consisting of a hydroxyl        group (—OH) and a carboxyl group (—COOH).        6. A method according to item 5, wherein said at least one        functional group of the non-metal coating is a hydroxyl group        (—OH).        7. A method according to any one of item 1 to 6, wherein said at        least one functional group of the non-metal coating is a silanol        group (—Si—OH).        8. A method according to any one of items 1 to 7, wherein the        non-metal coating comprises a plurality of functional groups.        9. A method according to any one of items 1 to 8, wherein prior        to forming the non-metal coating, said surface of the device or        the component, as applicable, is exposed to an oxygen or argon        plasma, in particular to an oxygen plasma, more particularly an        oxygen plasma under ion bombardment conditions.        10. A method according to any one of items 1 to 9, wherein the        non-metal coating is formed by plasma deposition.        11. A method according to item 10, wherein the non-metal coating        is formed by plasma deposition under ion bombardment conditions.        12. A method according to any one of items 1 to 11, wherein the        non-metal coating comprises silicon, oxygen and hydrogen.        13. A method according to item 12, wherein the forming the        non-metal coating comprising silicon, oxygen and hydrogen        comprises ionizing a gas comprising at least one of an        organosilicon or a silicon hydride.        14. A method according to item 13, wherein the gas comprises an        organosilicon.        15. A method according to item 14, wherein the organosilicon is        selected from the group consisting of trimethylsilane,        triethylsilane, trimethoxysilane, triethoxysilane,        tetramethylsilane, tetraethylsilane, tetramethoxysilane,        tetraethoxysilane, hexamethylcyclotrisiloxane,        tetramethylcyclotetrasiloxane, tetraethylcyclotetrasiloxane,        octamethylcyclotetrasiloxane, hexamethyldisiloxane,        bistrimethylsilylmethane, and mixtures thereof.        16. A method according to item 15, wherein the organosilicon is        selected from the group consisting of trimethylsilane,        triethylsilane, tetramethylsilane, tetraethylsilane,        bistrimethylsilylmethane and mixtures thereof        17. A method according to item 16, wherein the organosilicon is        tetramethylsilane.        18. A method according to item 13, wherein the gas comprises a        silicon hydride, in particular a silicon hydride selected from        the group consisting of SiH₄ (silicon tetrahydride), Si₂H₆        (disilane), and mixtures thereof.        19. A method according to any one of items 13 to 18, wherein the        gas further comprises oxygen.        20. A method according to any one of items 12 to 19, wherein the        non-metal coating further comprises carbon.        21. A method according to item 20, wherein the non-metal coating        is a diamond-like glass containing on a hydrogen free basis at        least about 20 atomic percent carbon and at least about 30        atomic percent of silicon+oxygen.        22. A method according to item 21, wherein the diamond-like        glass contains on a hydrogen free basis at least about 25 atomic        percent carbon, about 15 to about 50 atomic percent of silicon        and about 15 to about 50 atomic percent oxygen.        23. A method according to item 22, wherein the diamond-like        glass contains on a hydrogen free basis about 30 to about 60        atomic percent carbon, about 20 to about 45 atomic percent of        silicon and about 20 to about 45 atomic percent oxygen.        24. A method according to item 23, wherein the diamond-like        glass contains on a hydrogen free basis about 30 to about 50        atomic percent carbon, about 25 to about 35 atomic percent of        silicon and about 25 to about 45 atomic percent oxygen.        25. A method according to item 24, wherein the diamond-like        glass contains on a hydrogen free basis about 30 to about 36        atomic percent carbon, about 26 to about 32 atomic percent of        silicon and about 35 to about 41 atomic percent oxygen.        26. A method according to any one of items 12 to 25, wherein the        silicon to oxygen ratio in the non-metal coating is less than        two.        27. A method according to any one of items 1 to 26, wherein the        non-metal coating is exposed to an oxygen plasma or a corona        treatment prior to applying the composition comprising an at        least partially fluorinated compound comprising at least one        functional group, in particular an oxygen plasma, more        particular an oxygen plasma under ion bombardment conditions.        28. A method according to any one of items 1 to 27, wherein said        at least one functional group of the at least partially        fluorinated compound has a hydrolysable group.        29. A method according to any one of items 1 to 28, wherein said        at least one functional group of the at least partially        fluorinated compound is a silane group.        30. A method according to item 29, wherein the silane group        comprises at least one hydrolysable group, in particular at        least two hydrolysable groups, and more particularly three        hydrolysable groups.        31. A method according to any one of items 1 to 30, wherein said        at least partially fluorinated compound comprises a        polyfluoropolyether segment, in particular a perfluorinated        polyfluoropolyether segment.        32. A method according to any one of item 31, wherein said at        least partially fluorinated compound comprises a perfluorinated        polyfluoropolyether segment, where in the repeating units of the        perfluorinated polyfluoropolyether segment the number of carbon        atoms in sequence is at most 6, in particular at most 4, more        particular at most 3 and most particular at most 2.        33. A method according to any one of items 1 to 32, wherein the        at least partially fluorinated compound comprising at least one        functional group is a polyfluoropolyether silane, in particular        a multifunctional polyfluoropolyether silane, and more        particularly a difunctional polyfluoropolyether silane.        34. A method according to item 33, wherein the        polyfluoropolyether segment(s) of the polyfluoropolyether silane        is (are) not linked to the functional silane group(s) via a        functionality that includes nitrogen-silicon bond or a        sulfur-silicon bond.        35. A method according to item 33 or item 34, wherein the        polyfluoropolyether segment(s) of the polyfluoropolyether silane        is (are) linked to the functional silane group(s) via a        functionality that includes a carbon-silicon bond.        36. A method according to item 35, wherein the        polyfluoropolyether segment(s) of the polyfluoropolyether silane        is (are) linked to the functional silane group(s) via a        —C(R)₂—Si functionality where R is independently hydrogen or a        C₁₋₄ alkyl group, more particular hydrogen.        37. A method according to item 36, wherein the        polyfluoropolyether segment(s) of the polyfluoropolyether silane        is (are) linked to the functional silane group(s) via a        —(CR₂)_(k)—C(R)₂—Si functionality where k is at least 2 and        where R is independently hydrogen or a C₁₋₄ alkyl group, more        particular hydrogen.        38. A method according to any one of items 33 to 36, wherein the        polyfluoropolyether silane is of Formula Ia:

R_(f)[Q-[C(R)₂—Si(Y)_(3-x)(R^(1a))_(x)]_(y)]_(z)  Ia

-   -   wherein:        -   R_(f) is a monovalent or multivalent polyfluoropolyether            segment;        -   Q is an organic divalent or trivalent linking group;        -   each R is independently hydrogen or a C₁₋₄ alkyl group;        -   each Y is independently a hydrolysable group;        -   R^(1a) is a C₁₋₈ alkyl or phenyl group;        -   x is 0 or 1 or 2;        -   y is 1 or 2; and        -   z is 1, 2, 3, or 4.            39. A method according to item 38, wherein the            polyfluoropolyether segment, R_(f), comprises perfluorinated            repeating units selected from the group consisting of            —(C_(n)F_(2n)O)—, —(CF(Z)O)—, —(CF(Z)C_(n)F_(2n)O)—,            —(C_(n)F_(2n)CF(Z)O)—, —(CF₂CF(Z)O)—, and combinations            thereof; wherein n is an integer from 1 to 6 and Z is a            perfluoroalkyl group, an oxygen-containing perfluoroalkyl            group, a perfluoroalkoxy group, or an oxygen-substituted            perfluoroalkoxy group, each of which can be linear,            branched, or cyclic, and have 1 to 5 carbon atoms and up to            4 oxygen atoms when oxygen-containing or oxygen-substituted            and wherein for repeating units including Z the number of            carbon atoms in sequence is at most 6.            40. A method according to item 39, wherein n is an integer            from 1 to 4 and wherein for repeating units including Z the            number of carbon atoms in sequence is at most four.            41. A method according to item 39 or item 40, wherein n is            an integer from 1 to 3 and wherein for repeating units            including Z the number of carbon atoms in sequence is at            most three.            42. A method according to any one of items 39 to 41, wherein            the polyfluoropolyether segment, R_(f), comprises            perfluorinated repeating units selected from the group            consisting of —(C_(n)F_(2n)O)—, —(CF(Z)O)—, and combinations            thereof; wherein n is 1 or 2 and Z is an —CF₃ group.            43. A method according to any one of items 38 to 40, wherein            z is 1 and R_(f) is selected from the group consisting of            C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, CF₃O(C₂F₄O)_(p)CF₂—,            C₃F₇O(CF(CF₃)CF₂O)_(p)CF₂CF₂—, C₃F₇O(CF₂CF₂CF₂O)_(p)CF₂CF₂—,            C₃F₇O(CF₂CF₂CF₂O)_(p)CF(CF₃)— and            CF₃O(CF₂CF(CF₃)O)_(p)(CF₂O)X—, wherein X is CF₂—, C₂F₄—,            C₃F₆—, C₄F₈— and wherein the average value of p is 3 to 50.            44. A method according to any one of items 38 to 40, wherein            z is 2, and R_(f) is selected from the group consisting of            —CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂—,            —CF(CF₃)O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, —CF₂O(C₂F₄O)_(p)CF₂—,            —(CF₂)₃O(C₄F₈O)_(p)(CF₂)₃—,            —CF(CF₃)—(OCF₂CF(CF₃))_(p)O—C_(t)F_(2t)—O(CF(CF₃)CF₂O)_(p)CF(CF₃)—,            wherein t is 2, 3 or 4 and wherein m is 1 to 50, and p is 3            to 40.            45. A method according to item 44, wherein R_(f) is selected            from the group consisting of —CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂—,            —CF₂O(C₂F₄O)_(p)CF₂—, and            —CF(CF₃)—(OCF₂CF(CF₃))_(p)O—(C_(t)F_(2t))—O(CF(CF₃)CF₂O)_(p)CF(CF₃)—,            and wherein t is 2, 3 or 4, and wherein the average value of            m+p or p+p or p is from about 4 to about 24.            46. A method according to any one of items 38 to 45, wherein            Q is selected from the group consisting of            —C(O)N(R)—(CH₂)_(k)—, —S(O)₂N(R)—(CH₂)_(k)—, —(CH₂)_(k)—,            —CH₂O—(CH₂)_(k)—, —C(O)S—(CH₂)_(k)—,            —CH₂OC(O)N(R)—(CH₂)_(k)—, and

wherein R is hydrogen or C₁₋₄ alkyl, and k is 2 to about 25.47. A method according to item 46, wherein Q is selected from the groupconsisting of —C(O)N(R)(CH₂)₂—, —OC(O)N(R)(CH₂)₂—, —CH₂O(CH₂)₂—, or—CH₂—OC(O)N(R)—(CH₂)₂—,wherein R is hydrogen or C₁₋₄ alkyl and y is 1.48. A method according to any one of items 36 to 47, wherein R ishydrogen.49. A method according to any one of items 38 to 48, wherein x is 0.50. A method according to item 28 or item 30 or any one of items 38 to49, wherein each hydrolysable group is independently selected from thegroup consisting of hydrogen, halogen, alkoxy, acyloxy, polyalkyleneoxy,and aryloxy groups.51. A method according to item 50, wherein each hydrolysable group isindependently selected from the group consisting of alkoxy, acyloxy,aryloxy, and polyalkyleneoxy groups.52. A method according to item 50 or item 51, wherein each hydrolysablegroup is independently an alkoxy group, in particular an alkoxy group—OR′ wherein each R′ is independently a C₁₋₆alkyl, more particularly aC₁₋₄ alkyl.53. A method according to any one of items 38 to 42 or any one of itemsof items 44 to 52, wherein R_(f) is —CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂—, andQ-C(R)₂—Si(Y′)_(3-x)(R^(1a))_(x) is C(O)NH(CH₂)₃Si(OR′)₃, wherein R′ ismethyl or ethyl and wherein m is 1 to 50 and p is 3 to 40, in particularwherein the average value of m+p or p+p or p is from about 4 to about24, more particularly wherein m and p are each about 9 to 12.54. A method according to any one of items 31 to 53, wherein the weightaverage molecular weight of the polyfluoropolyether segment is about1000 or higher, in particular about 1800 or higher.55. A method according to any one of items 33 to 53, wherein the amountof polyfluoropolyether silane having a polyfluoropolyether segmenthaving a weight average molecular weight less than 750 is not more than10% by weight of total amount of polyfluoropolyether silane, inparticular not more than 5% by weight of total amount ofpolyfluoropolyether silane, more particularly not more than 1% by weightof total amount of polyfluoropolyether silane, and most particular 0% byweight of total amount of polyfluoropolyether silane.56. A method according to any one of items 30 to 55 as dependentdirectly or indirectly on item 5 or item 6, wherein the non-metalcoating is substantially free of amine, amido and/or thiol functionalgroups, in particular the non-metal coating is free of amine, amidoand/or thiol functional groups57. A method according to any one of items 1 to 56, wherein thenon-metal coating is substantially free of fluorine, in particular freeof fluorine.58. A method according to any one of items 1 to 57, wherein thecomposition comprising an at least partially fluorinated compoundcomprising at least one a functional group further comprises an organicsolvent.59. A method according to item 58, wherein the organic solvent is afluorinated solvent and/or a lower alcohol.60. A method according to item 58 or item 59, wherein the compositioncomprising an at least partially fluorinated compound comprising atleast one a functional group further comprises an acid.61. A method according to any one of items 1 to 60, wherein thecomposition comprising an at least partially fluorinated compoundcomprising at least one functional group further comprises water.62. A method according to any one of items 1 to 61, wherein thecomposition comprising an at least partially fluorinated compoundcomprising at least one functional group further comprises anon-fluorinated cross-linking agent, in particular a cross-linking agentcomprising one or more non-fluorinated compounds, each compound havingat least two hydrolysable groups per molecule.63. A method according to item 62, wherein the non-fluorinated compoundis a compound in accordance to Formula II:

Si(Y²)_(4-g)(R⁵)_(g)  II

-   -   where R⁵ represents a non-hydrolysable group;    -   Y² represents a hydrolysable group; and    -   g is 0, 1 or 2.        64. A method according to item 62 or 63, wherein the        cross-linking agent comprises a compound selected from group        consisting of tetramethoxysilane, tetraethoxysilane,        tetrapropoxysilane, tetrabutoxysilane, methyl triethoxysilane,        dimethyldiethoxysilane, octadecyltriethoxy-silane,        3-glycidoxypropyltriethoxysilane,        3-aminopropyl-trimethoxysilane, 3-aminopropyltriethoxysilane        3-trimethoxysilylpropylmethacrylate, and mixtures thereof.        65. A method according to any one of items 1 to 64, wherein the        composition comprising an at least partially fluorinated        compound comprising at least one functional group is applied by        spraying, dipping, rolling, brushing, spreading, spin coating or        flow coating, in particular by spraying or dipping.        66. A method according to any one of items 1 to 65, wherein        after applying the composition, the method further comprises a        step of curing.        67. A method according to item 66, wherein the curing is carried        out at an elevated temperature in the range from about 40° C. to        about 300° C.        68. A method according to any one of items 1 to 67, wherein the        non-metal coating is formed on said surface of the device or        said surface of the component of the device, as applicable, such        that the non-metal coating is covalently bonded to said surface.        69. A method according to any one of items 1 to 68, where said        surface of the device or said surface of the component of the        device, as applicable, is a surface that is or will come in        contact with a medicament or a medicinal formulation during        storage or delivery from the medicinal inhalation device.        70. A method according to any one of items 1 to 69, where said        surface of the device or said surface of the component of the        device, as applicable, is a surface that comes in contact with a        movable component of the device or is a surface of a movable        component of the device.        71. A method according to any one of items 1 to 70, where said        medicinal inhalation device is a metered dose inhaler or a dry        powder inhaler.        72. A medicinal inhalation device made according to item 1 or        any one of items 3 to 71 as directly or indirectly dependent on        item 1.        73. A component of a medical inhalation device made according to        item 2 or any one of items 3 to 71 as directly or indirectly        dependent on item 2.        74. A medicinal inhalation device comprising a non-metal coating        on at least a portion of a surface of the device and a        fluorine-containing coating bonded to the non-metal coating        wherein the fluorine-containing coating comprises an at least        partially fluorinated compound comprising at least one        functional group which shares at least one covalent bond with        the non-metal coating.        75. A component of a medicinal inhalation device comprising a        non-metal coating on at least a portion of a surface of the        component, and a fluorine-containing coating bonded to the        non-metal coating wherein the fluorine-containing coating        comprises an at least partially fluorinated compound comprising        at least one functional group which shares at least one covalent        bond with the non-metal coating.        76. A device according to item 74 or a component according to        item 75, wherein the fluorine-containing coating is covalently        bonded to the non-metal coating through a plurality of covalent        bonds.        77. A device according to item 74 or item 76 as dependent on        item 74 or a component according to item 75 or item 76 as        dependent on item 75, wherein the fluorine-containing coating is        covalently bonded to the non-metal coating through a plurality        of covalent bonds including bonds in O—Si groups, in particular        bonds in Si—O—Si groups.        78. A device according to item 74 or any of one of items 76 to        77 as directly or indirectly dependent on item 74, or a        component according to item 75 or any of one items 76 to 77 as        directly or indirectly dependent on item 75, wherein the        non-metal coating comprises silicon and oxygen.        79. A device according to item 78 as directly or indirectly        dependent on item 74, or a component according to item 78 as        directly or indirectly dependent on item 75, wherein the        non-metal coating further comprises carbon.        80. A device according to item 78 or 79 as directly or        indirectly dependent on item 74, or a component according to        item 78 or 79 as directly or indirectly dependent on item 75,        wherein the silicon to oxygen ratio in the non-metal coating is        less than two.        81. A device according to item 74 or any of one of items 76 to        80 as directly or indirectly dependent on item 74, or a        component according to item 75 or any of one of items 76 to 80        as directly or indirectly dependent on item 75, wherein the        non-metal coating is substantially free of fluorine, more        particularly free of fluorine.        82. A device according to item 74 or any one of items 76 to 81        as directly or indirectly dependent on item 74, or a component        according to item 75 or any one of items 76 to 81 as directly or        indirectly dependent on item 75, wherein the non-metal coating        is covalently bonded to the at least a portion of a surface of        the device or the component, respectively.        83. A device according to item 74 or any one of items 76 to 82        as directly or indirectly dependent on item 74, or a component        according to item 75 or any of one of items 76 to 82 as directly        or indirectly dependent on item 75, wherein the non-metal        coating is a plasma-deposited coating.        84. A device according to item 83 as directly or indirectly        dependent on item 74, or a component according to item 83 as        directly or indirectly dependent on item 75, wherein the        non-metal coating is a plasma-deposited coating deposited under        conditions of ion bombardment.        85. A device according to item 74 or any one of items 76 to 84        as directly or indirectly dependent on item 74, or a component        according to item 75 or any one of items 76 to 84 as directly or        indirectly dependent on item 75, wherein the non-metal coating        is a diamond-like glass coating.        86. A device according to item 85 as directly or indirectly        dependent on item 74, or a component according to item 85 as        directly or indirectly dependent on item 75, wherein the        diamond-like glass coating contains on a hydrogen free basis at        least about 20 atomic percent carbon and at least about 30        atomic percent of silicon+oxygen.        87. A device according to item 86 as directly or indirectly        dependent on item 74, or a component according to item 86 as        directly or indirectly dependent on item 75, wherein the        diamond-like glass coating contains on a hydrogen free basis at        least about 25 atomic percent carbon, about 15 to about 50        atomic percent of silicon and about 15 to about 50 atomic        percent oxygen.        88. A device according to item 87 as directly or indirectly        dependent on item 74, or a component according to item 87 as        directly or indirectly dependent on item 75, wherein the        diamond-like glass coating contains on a hydrogen free basis        about 30 to about 60 atomic percent carbon, about 20 to about 45        atomic percent of silicon and about 20 to about 45 atomic        percent oxygen.        89. A device according to item 88 as directly or indirectly        dependent on item 74, or a component according to item 88 as        directly or indirectly dependent on item 75, wherein the        diamond-like glass coating contains on a hydrogen free basis        about 30 to about 50 atomic percent carbon, about 25 to about 35        atomic percent of silicon and about 25 to about 45 atomic        percent oxygen.        90 A device according to item 89 as directly or indirectly        dependent on item 74, or a component according to item 89 as        directly or indirectly dependent on item 75, wherein the        diamond-like glass coating contains on a hydrogen free basis        about 30 to about 36 atomic percent carbon, about 26 to about 32        atomic percent of silicon and about 35 to about 41 atomic        percent oxygen.        91. A device according to item 74 or any of one of items 76 to        90 as directly or indirectly dependent on item 74, or a        component according to item 75 or any of one of items 76 to 90        as directly or indirectly dependent on item 75, wherein the at        least one functional group of the at least partially fluorinated        compound is a silane group.        92. A device according to item 74 or any of one of items 76 to        91 as directly or indirectly dependent on item 74, or a        component according to item 75 or any of one of items 76 to 91        as directly or indirectly dependent on item 75, wherein the at        least partially fluorinated compound comprises a        polyfluoropolyether segment, in particular a perfluorinated        polyfluoropolyether segment.        93. A device according to item 74 or any of one of items 76 to        92 as directly or indirectly dependent on item 74, or a        component according to item 75 or any of one of items 76 to 92        as directly or indirectly dependent on item 75, wherein the at        least partially fluorinated compound comprises a perfluorinated        polyfluoropolyether segment, where in the repeating units of the        perfluorinated polyfluoropolyether segment the number of carbon        atoms in sequence is at most 6, in particular at most 4, more        particular at most 3 and most particular at most 2.        94. A device according to item 74 or any of one of items 76 to        93 as directly or indirectly dependent on item 74, or a        component according to item 75 or any of one of items 76 to 93        as directly or indirectly dependent on item 75, wherein the at        least partially fluorinated compound comprising at least one        functional group is a polyfluoropolyether silane, in particular        a multifunctional polyfluoropolyether silane, and more        particularly a difunctional polyfluoropolyether silane.        95. A device according to item 94 as directly or indirectly        dependent on item 74, or a component according to item 94 as        directly or indirectly dependent on item 75, wherein the        polyfluoropolyether segment(s) is (are) not linked to the silane        group(s) via a functionality that includes nitrogen-silicon bond        or a sulfur-silicon bond.        96. A device according to item 94 or item 95 as directly or        indirectly dependent on item 74, or a component according to        item 94 or item 95 as directly or indirectly dependent on item        75, wherein the polyfluoropolyether segment(s) is (are) linked        to the silane group(s) via a functionality that includes a        carbon-silicon bond, in particular via a —C(R)₂—Si functionality        where R is independently hydrogen or a C₁₋₄ alkyl group, more        particular via a —(CR₂)_(k)—C(R)₂—Si functionality where k is at        least 2 and where R is independently hydrogen or a C₁₋₄ alkyl        group.        97. A device according to item 94 or item 95 as directly or        indirectly dependent on item 74, or a component according to        item 94 or item 95 as directly or indirectly dependent on item        75, wherein the fluorine-containing coating is a        polyfluoropolyether-containing coating comprising        polyfluoropolyether silane entities of the following Formula Ib:

R_(f)[Q-[C(R)₂—Si(O—)_(3-x)(R^(1a))_(x)]_(y)]_(z)  Ib

which shares at least one covalent bond with the non-metal coating; and

-   -   wherein:        -   R_(f) is a monovalent or multivalent polyfluoropolyether            segment;        -   Q is an organic divalent or trivalent linking group;        -   each R is independently hydrogen or a C₁₋₄ alkyl group;        -   R^(1a) is a C₁₋₈ alkyl or phenyl group;    -   x is 0 or 1 or 2;    -   y is 1 or 2; and    -   z is 1, 2, 3, or 4.        98. A device according to item 97 as directly or indirectly        dependent on item 74, or a component according to item 97 as        directly or indirectly dependent on item 75, wherein the at        least on covalent bond shared with the non-metal coating is a        bond to an oxygen atom in Si(O—)_(3-x).        99. A device according to item 97 or item 98 as directly or        indirectly dependent on item 74, or a component according to        item 97 or item 98 as directly or indirectly dependent on item        75, wherein the polyfluoropolyether segment, R_(f), comprises        perfluorinated repeating units selected from the group        consisting of —(C_(n)F_(2n)O)—, —(CF(Z)O)—,        —(CF(Z)C_(n)F_(2n)O)—, —(C_(n)F_(2n)CF(Z)O)—, —(CF₂CF(Z)O)—, and        combinations thereof; wherein n is an integer from 1 to 6 and Z        is a perfluoroalkyl group, an oxygen-containing perfluoroalkyl        group, a perfluoroalkoxy group, or an oxygen-substituted        perfluoroalkoxy group, each of which can be linear, branched, or        cyclic, and have 1 to 5 carbon atoms and up to 4 oxygen atoms        when oxygen-containing or oxygen-substituted and wherein for        repeating units including Z the number of carbon atoms in        sequence is at most 6.        100. A device according to item 99 as directly or indirectly        dependent on item 74, or a component according to item 99 as        directly or indirectly dependent on item 75, wherein n is an        integer from 1 to 4 and wherein for repeating units including Z        the number of carbon atoms in sequence is at most four.        101. A device according to item 100 as directly or indirectly        dependent on item 74, or a component according to item 100 as        directly or indirectly dependent on item 75, wherein n is an        integer from 1 to 3 and wherein for repeating units including Z        the number of carbon atoms in sequence is at most three, more        particularly the polyfluoropolyether segment, R_(f), comprises        perfluorinated repeating units selected from the group        consisting of —(C_(n)F_(2n)O)—, —(CF(Z)O)—, and combinations        thereof; wherein n is 1 or 2 and Z is an —CF₃ group.        102. A device according to any one of items 97 to 100 as        directly or indirectly dependent on item 74, or a component        according to any one of items 97 to 100 as directly or        indirectly dependent on item 75, wherein z is 1 and R_(f) is        selected from the group consisting of        C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, CF₃O(C₂F₄O)_(p)CF₂—,        C₃F₇O(CF(CF₃)CF₂O)_(p)CF₂CF₂—, C₃F₇O(CF₂CF₂CF₂O)_(p)CF₂CF₂—,        C₃F₇O(CF₂ CF₂CF₂O)_(p)CF(CF₃)— and        CF₃O(CF₂CF(CF₃)O)_(p)(CF₂O)X—, wherein X is CF₂—, C₂F₄—, C₃F₆—,        C₄F₈— and wherein the average value of p is 3 to 50.        103. A device according to any one of items 97 to 100 as        directly or indirectly dependent on item 74, or a component        according to any one of items 97 to 101 as directly or        indirectly dependent on item 75, wherein z is 2, and R_(f) is        selected from the group consisting of        —CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂—,        —CF(CF₃)O(CF(CF₃)CF₂O)_(p)CF(CF₃)—        —CF(CF₃)—(OCF₂CF(CF₃))_(p)O—C_(t)F_(2t)—O(CF(CF₃)CF₂O)_(p)CF(CF₃)—,        —CF₂O(C₂F₄O)_(p)CF₂—, —(CF₂)₃O(C₄F₈O)_(p)(CF₂)₃—, wherein t is        2, 3 or 4 and wherein m is 1 to 50, and p is 3 to 40.        104. A device according to item 103 as directly or indirectly        dependent on item 74, or a component according to item 103 as        directly or indirectly dependent on item 75, wherein R_(f) is        selected from the group consisting of        —CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂—, —CF₂O(C₂F₄O)_(p)CF₂—, and        —CF(CF₃)—(OCF₂CF(CF₃))_(p)O—(C_(t)F_(2t))—O(CF(CF₃)CF₂O)_(p)CF(CF₃)—,        and wherein t is 2, 3 or 4, and wherein the average value of m+p        or p+p or p is from about 4 to about 24.        105. A device according to any one of items 97 to 104 as        directly or indirectly dependent on item 74, or a component        according to any one of items 97 to 104 as directly or        indirectly dependent on item 75, wherein Q is selected from the        group consisting of —C(O)N(R)—(CH₂)_(k)—, —S(O)₂N(R)—(CH₂)_(k)—,        —(CH₂)_(k)—, —CH₂O—(CH₂)_(k)—, —C(O)S—(CH₂)_(k)—,        —CH₂OC(O)N(R)—(CH₂)_(k)—, and

wherein R is hydrogen or C₁₋₄ alkyl, and k is 2 to about 25.106. A device according to item 105 as directly or indirectly dependenton item 74, or a component according to item 105 as directly orindirectly dependent on item 75, wherein Q is selected from the groupconsisting of —C(O)N(R)(CH₂)₂—, —OC(O)N(R)(CH₂)₂—, —CH₂O(CH₂)₂—, or—CH₂—OC(O)N(R)—(CH₂)₂—, wherein R is hydrogen or C₁₋₄ alkyl and y is 1.107. A device according to any one of items 96 to 106 as directly orindirectly dependent on item 74, or a component according to any one ofitems 96 to 106 as directly or indirectly dependent on item 75, whereinR is hydrogen.108. A device according to any one of items 97 to 107 as directly orindirectly dependent on item 74, or a component according to any one ofitems 97 to 107 as directly or indirectly dependent on item 75, whereinx is 0.109. A device according to any one of items 97 to 101 or any one ofitems 103 to 108 as directly or indirectly dependent on item 74, or acomponent according to any one of items 97 to 101 or any one of items103 to 108 as directly or indirectly dependent on item 75, wherein R_(f)is —CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂—, and Q-C(R)₂—Si(O—)_(3-x)(R^(1a))_(x)is C(O)NH(CH₂)₃Si(O—)₃ and wherein m is 1 to 50 and p is 3 to 40, inparticular wherein the average value of m+p or p+p or p is from about 4to about 24, more particularly wherein m and p are each about 9 to 12.110. A device according to any one of items 92 to 109 as directly orindirectly dependent on item 74, or a component according to any one ofitems 92 to 109 as directly or indirectly dependent on item 75, whereinthe weight average molecular weight of the polyfluoropolyether segmentis about 1000 or higher, in particular about 1800 or higher.111. A device according to any one of items 92 to 110 as directly orindirectly dependent on item 74, or a component according to any one ofitems 92 to 110 as directly or indirectly dependent on item 75, whereinthe weight average molecular weight of the polyfluoropolyether segmentis about 6000 or less, in particular about 4000 or less.112. A device according to any one of items 94 to 111 as directly orindirectly dependent on item 74, or a component according to any one ofitems 94 to 111 as directly or indirectly dependent on item 75, whereinthe amount of polyfluoropolyether silane having a polyfluoropolyethersegment having a weight average molecular weight less than 750 is notmore than 10% by weight of total amount of polyfluoropolyether silane,in particular not more than 5% by weight of total amount ofpolyfluoropolyether silane, more particularly not more than 1% by weightof total amount of polyfluoropolyether silane, and most particular 0% byweight of total amount of polyfluoropolyether silane.113. A device according to any one of items 91 to 112 as directly orindirectly dependent on item 74, or a component according to any one ofitems 92 to 112 as directly or indirectly dependent on item 75, whereinthe non-metal coating is substantially free of nitrogen and/or sulfur,in particular free of nitrogen and/or sulfur.114. A medicinal inhalation device comprising a non-metal coating plasmadeposited on at least a portion of a surface of the device, said coatingbeing plasma deposited under ion bombardment conditions and beingsubstantially free of fluorine, in particular free of fluorine.115. A component of a medicinal inhalation device comprising a non-metalcoating plasma deposited on at least a portion of a surface of thecomponent, said coating being plasma deposited under ion bombardmentconditions and being substantially free of fluorine, in particular freeof fluorine.116. A device according to item 114 or a component according to item115, wherein the non-metal coating is covalently bonded to the at leasta portion of a surface of the device or the component, respectively.117. A device according to item 114 or item 116 as dependent on item114, or a component according to item 115 or item 116 as dependent onitem 115, wherein the non-metal coating comprises silicon, oxygen andhydrogen.118. A device according to item 117 as directly or indirectly dependenton item 114, or a component according to item 117 as directly orindirectly dependent on item 115, wherein the non-metal coating furthercomprises carbon.119. A device according to item 117 or item 118 as directly orindirectly dependent on item 114, or a component according to item 117or item 118 as directly or indirectly dependent on item 115, wherein thesilicon to oxygen ratio in the non-metal coating is less than two.120. A medicinal inhalation device comprising a diamond-like glasscoating on at least a portion of a surface of the device.121. A component of a medicinal inhalation device comprising adiamond-like glass coating on at least a portion of a surface of thecomponent.122. A device according to item 120, or a component according to item121, wherein the diamond-like glass coating contains on a hydrogen freebasis at least about 20 atomic percent carbon and at least about 30atomic percent of silicon+oxygen.123. A device according to item 122 as dependent on item 120, or acomponent according to item 122 as dependent on item 121, wherein thediamond-like glass coating contains on a hydrogen free basis at leastabout 25 atomic percent carbon, about 15 to about 50 atomic percent ofsilicon and about 15 to about 50 atomic percent oxygen.124. A device according to item 123 as directly or indirectly dependenton item 120, or a component according to item 123 as directly orindirectly dependent on item 121, wherein the diamond-like glass coatingcontains on a hydrogen free basis about 30 to about 60 atomic percentcarbon, about 20 to about 45 atomic percent of silicon and about 20 toabout 45 atomic percent oxygen.125. A device according to item 124 as directly or indirectly dependenton item 120, or a component according to item 124 as directly orindirectly dependent on item 121, wherein the diamond-like glass coatingcontains on a hydrogen free basis about 30 to about 50 atomic percentcarbon, about 25 to about 35 atomic percent of silicon and about 25 toabout 45 atomic percent oxygen.126. A device according to item 125 as directly or indirectly dependenton item 120, or a component according to item 125 as directly orindirectly dependent on item 121, wherein the diamond-like glass coatingcontains on a hydrogen free basis about 30 to about 36 atomic percentcarbon, about 26 to about 32 atomic percent of silicon and about 35 toabout 41 atomic percent oxygen.127. A device according to item 120 or any one of items 122 to 126 asdirectly or indirectly dependent on item 120, or a component accordingto item 120 or any one of items 122 to 126 as directly or indirectlydependent on item 121, wherein the silicon to oxygen ratio in thediamond-like glass coating is less than two.128. A device or a component according to any one of items 74 to 127, asapplicable, where said surface of the device or said surface of thecomponent of the device, as applicable, is a surface that is or willcome in contact with a medicament or a medicinal formulation duringstorage or delivery from the medicinal inhalation device.129. A device or a component according to any one of items 74 to 128, asapplicable, where said surface of the device or said surface of thecomponent of the device, as applicable, is a surface that comes incontact with a movable component of the device or is a surface of amovable component of the device.130. A device or a component according to any one of items 74 to 129where said medicinal inhalation device is a metered dose inhaler or adry powder inhaler.131. A component according to item 73 or item 75 or any one of items 76to 113 as directly or indirectly dependent on item 75 or item 115 or anyone of items 116 to 119 as directly or indirectly dependent on item 115or item 121 or any one of items 122 to 127 as directly or indirectlydependent on item 121, wherein the component is a component of a metereddose inhaler and the component is selected from the group consisting ofan actuator, an aerosol container, a ferrule, a valve body, a valve stemand a compression spring.132. A component according to item 73 or item 75 or any one of items 76to 113 as directly or indirectly dependent on item 75 or item 115 or anyone of items 116 to 119 as directly or indirectly dependent on item 115or item 121 or any one of items 122 to 127 as directly or indirectlydependent on item 121, wherein the component is a component of a drypowder inhaler and the component is selected from the group consistingof a powder container, an component used to open sealed powdercontainer, a component that defines at least in part a deagglomerationchamber, a component of a deaglomeration system, a component thatdefines at least in part a flow channel, a dose-transporting component,a component that defines at least in part a mixing chamber, a componentthat defines at least in part an actuation chamber, a mouthpiece and anosepiece.133. A component according to item 73 or item 75 or any one of items 76to 113 as directly or indirectly dependent on item 75 or item 115 or anyone of items 116 to 119 as directly or indirectly dependent on item 115or item 121 or any one of items 122 to 127 as directly or indirectlydependent on item 121, wherein the component is a component of abreath-actuating device or a component of a breath-coordinating deviceor a spacer or a component of a spacer or a component of a dose counterfor a medicinal inhalation device.134. A device according to item 72 or item 74 or any one of items 76 to113 as directly or indirectly dependent on item 74 or item 114 or anyone of items 116 to 119 as directly or indirectly dependent on item 114or item 120 or any one of items 122 to 127 as directly or indirectlydependent on item 120, wherein the device is a metered dose inhaler andthe inhaler contains a medicinal aerosol formulation comprising amedicament and HFA 134a and/or HFA 227135. A device according to item 134, wherein the medicinal aerosolformulation is substantially free of ethanol.136. A device according to item 135, wherein the medicinal aerosolformulation is free of ethanol.137. A device according to any one of items 134 to 136, wherein themedicinal aerosol formulation is substantially free of surfactant.138. A device according to item 137, wherein the medicinal aerosolformulation is free of surfactant.139. A device according to any one of items 134 to 138, wherein themedicinal aerosol formulation comprises a medicament that is dispersedsaid formulation.140. A device according to any one of items 134 to 139, wherein themedicinal aerosol formulation medicinal formulation comprises amedicament selected from the group consisting of albuterol, terbutaline,ipratropium, oxitropium, tiotropium, beclomethasone, flunisolide,budesonide, mometasone, ciclesonide, cromolyn sodium, nedocromil sodium,ketotifen, azelastine, ergotamine, cyclosporine, salmeterol,fluticasone, formoterol, procaterol, indacaterol, TA2005, omalizumab,zileuton, insulin, pentamidine, calcitonin, leuprolide,alpha-1-antitrypsin, interferon, triamcinolone, and pharmaceuticallyacceptable salts and esters thereof and mixtures thereof.

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the application,guidance is provided through lists of examples, which examples can beused individually and in various combinations. In each instance, therecited list serves only as a representative group and should not beinterpreted as an exclusive list

BRIEF DESCRIPTION OF DRAWINGS

The invention will now be described with reference to the accompanyingdrawings in which:

FIG. 1 a represents a schematic cross-sectional view of a pressurizedmetered dose inhaler known in the art and FIG. 1 b represents anenlarged view of a portion of the inhaler.

FIGS. 2 to 5 represent schematic cross-sectional views of furthermetered dose valves known in the art for use in pressurized metered doseinhalers.

FIGS. 6 and 7 each show a schematic cross-section of an exemplaryapparatus suitable for plasma depositing, in particular under conditionsof ion bombardment, a non-metal coating on at least a portion of thesurface of a substrate (e.g. a component of a medicinal inhalationdevice).

DETAILED DESCRIPTION

It is to be understood that the present invention covers allcombinations of particular, suitable, desirable, favorable, advantageousand preferred aspects of the invention described herein.

For better understanding of the present invention, in the following anexemplary, well known pressurized metered dose inhaler (FIG. 1) as wellas several known metered dose valves for pressurized metered doseinhalers (FIGS. 2 to 5) will be first described. In particular, FIG. 1 ashows a metered dose dispenser (100), in particular an inhaler,including an aerosol container (1) fitted with a metered dose valve (10)(shown in its resting position).

Aerosol containers for metered dose inhalers are typically made ofaluminum or an aluminum alloy. Aerosol containers may be made of othermaterials, such as stainless steel, glass, plastic and ceramics.

Returning to FIG. 1 a, the valve is typically affixed onto the containervia a cap or ferrule (11) (typically made of aluminum or an aluminumalloy) which is generally provided as part of the valve assembly. Theillustrated valve is a commercial valve marketed under the tradedesignation SPRAYMISER by 3M Company, St. Paul, Minn., USA. As shown inFIG. 1 a, the container/valve dispenser is typically provided with anactuator (5) including an appropriate patient port (6), such as amouthpiece. For administration to the nasal cavities the patient port isgenerally provided in an appropriate form (e.g. smaller diameter tube,often sloping upwardly) for delivery through the nose. Actuators aregenerally made of a plastic, for example polypropylene or polyethylene.As can be seen from FIG. 1 a, the inner walls (2) of the container andthe outer walls of the portion(s) of the metered dose valve locatedwithin the container defined a formulation chamber (3) in which aerosolformulation (4) is contained. Depending on the particular metered dosevalve and/or filling system, aerosol formulation may be filled into thecontainer either by cold-filling (in which chilled formulation is filledinto the container and subsequently the metered dose valve is fittedonto the container) or by pressure filling (in which the metered dosevalve is fitted onto the container and then formulation is pressurefilled through the valve into the container).

An aerosol formulation used in a metered dose inhaler typicallycomprises a medicament or a combination of medicaments and liquefiedpropellant selected from the group consisting of HFA 134a, HFA 227 andmixtures thereof. Aerosol formulations may, as desired or needed,comprise other excipients, such as surfactant, a co-solvent (e.g.ethanol), CO₂, or a particulate bulking agent. Medicament may beprovided in particulate form (generally having a median size in therange of 1 to 10 microns) suspended in the liquefied propellant.Alternatively medicament may be in solution (e.g. dissolved) in theformulation. In the event a combination of two or more medicaments isincluded, all the medicaments may be suspended or in solution oralternatively one or more medicaments may be suspended, while one ormore medicaments may be in solution. A medicament may be a drug,vaccine, DNA fragment, hormone or other treatment. The amount ofmedicament would be determined by the required dose per puff andavailable valve sizes, which are typically 25, 50 or 63 microlitres, butmay include 100 microlitres where particularly large doses are required.Suitable drugs include those for the treatment of respiratory disorders,e.g., bronchodilators, anti-inflammatories (e.g. corticosteroids),anti-allergies, anti-asthmatics, anti-histamines, and anti-cholinergicagents. Therapeutic proteins and peptides may also be employed fordelivery by inhalation. Exemplary drugs which may be employed fordelivery by inhalation include but are not limited to: albuterol,terbutaline, ipratropium, oxitropium, tiotropium, beclomethasone,flunisolide, budesonide, mometasone, ciclesonide, cromolyn sodium,nedocromil sodium, ketotifen, azelastine, ergotamine, cyclosporine,salmeterol, fluticasone, formoterol, procaterol, indacaterol, TA2005,omalizumab, zileuton, insulin, pentamidine, calcitonin, leuprolide,alpha-1-antitrypsin, interferons, triamcinolone, and pharmaceuticallyacceptable salts and esters thereof such as albuterol sulfate,formoterol fumarate, salmeterol xinafoate, beclomethasone dipropionate,triamcinolone acetonide, fluticasone propionate, tiotropium bromide,leuprolide acetate and mometasone furoate.

Embodiments, described in detail below, in accordance with the presentinvention are particularly useful in regard to metered dose inhalersincluding a medicinal aerosol formulation that include low amounts ofsurfactant (0.005 wt % with respect to the formulation); or issubstantially free (less than 0.0001 wt % with respect to drug) or freeof a surfactant. Alternatively or additionally, embodiments described indetail below, are particularly useful in metered dose inhalers includinga medicinal aerosol formulation that contains low amounts of ethanol(less than 5 wt % with respect to the formulation), or is substantiallyfree (less than 0.1 wt % with respect to the formulation) or free ofethanol.

The valve shown in FIG. 1 a, better viewed in FIG. 1 b, includes ametering chamber (12), defined in part by an inner valve body (13),through which a valve stem (14) passes. The valve stem, which is biasedoutwardly by a compression spring (15), is in sliding sealing engagementwith an inner tank seal (16) and an outer diaphragm seal (17). The valvealso includes a second valve body (20) in the form of a bottle emptier.

(For the sake of clarity in the description of various metered dosevalves, in particular those including at least two valve bodies, in thefollowing a valve body defining in part the metering chamber will bereferred to as a “primary” valve body, while other types of valve body,e.g. defining a pre-metering region, a pre-metering chamber, a springcage and/or a bottle emptier will be referred to as a “secondary” valvebody.)

Returning to FIG. 1 a, aerosol formulation (4) can pass from theformulation chamber into a pre-metering chamber (22) provided betweenthe secondary valve body (20) and the primary valve body (13) through anannular space (21) between the flange (23) of the secondary valve bodyand the primary valve body. To actuate (fire) the valve, the valve stem(14) is pushed inwardly relative to the container from its restingposition shown in FIGS. 1 a and b, allowing formulation to pass from themetering chamber through a side hole (19) in the valve stem and througha stem outlet (24) to an actuator nozzle (7) then out to the patient.When the valve stem (14) is released, formulation enters into the valve,in particular into the pre-metering chamber (22), through the annularspace (21) and thence from the pre-metering chamber through a groove(18) in the valve stem past the tank seal (16) into the metering chamber(12).

As mentioned above, FIGS. 2 to 5 show other known metered dose valvesused in pMDIs. Similar to the valve shown in FIG. 1, the valves of FIGS.2 to 5 are typically fitted via a ferrule onto an aerosol containerwhereby a formulation chamber is defined by the inner walls of thecontainer and the outer walls of the portion(s) of the valve locatedwithin the container. For the sake of ease in understanding andcomparison, similar components of the respective valves are identifiedwith like reference numbers in the Figures.

FIG. 2 shows a metered dose valve (10) of a type generally similar tothat disclosed and described in U.S. Pat. No. 5,772,085 (incorporatedherein by reference). The valve is shown in its resting position andincludes a valve body (20) and a valve stem (14). The valve stem, whichis biased outwardly under the pressure of the aerosol formulationcontained within the formulation container, is provided with an innerseal and an outer seal (16 and 17). Unlike the valves in FIG. 1 andFIGS. 3 to 5, which are push-to-fire type valves, the valve here is arelease-to-fire type valve. To actuate the valve, the valve stem (14) isfirst pushed upwards into the formulation chamber (not shown), so thatthe outer seal (17) passes inwardly beyond an outlet (25) provided inthe external portion of the valve body and the inner seal (16) thenpasses inwardly and disengages from the inner walls of the valve body,thus bringing the metering chamber (12) up into the formulation chamberso that formulation can enter the metering chamber (referred to as thepriming position of the valve) and then the valve stem is releasedmoving outwardly so that the inner seal re-engages the valve body andthe outer seal then passes outwardly beyond the outlet, bringing themetering chamber in communication with the outlet, so that formulationpasses through the outlet to the patient.

FIG. 3 shows a metered dose valve (10) of the type generally similar tothat disclosed and described in WO 2004/022142 (incorporated herein byreference). The valve is shown in its resting position and includes asecondary valve body (20) and a valve stem (14) that is biased outwardlyby a compression spring (15). The valve is provided with an inner seal(16) and outer diaphragm seal (17), with the valve stem being in slidingsealing engagement with the diaphragm seal. In this valve, the secondaryvalve body is in the form of a spring cage housing having three slots(21, two visible) providing communication between the formulationchamber (not shown) and a pre-metering chamber (22). This valve includesa transitory metering chamber formed upon actuation of the valve. Duringactuation of the valve, as the valve stem (14) is pushed inwardlyrelative to the container, a metering chamber (12, not visible) isformed between a lower surface (28) of a conical portion (27) of thevalve stem (14) and an upper, sloping surface (31) of a primary valvebody (13). Aerosol formulation passes around the shoulder (30) of theconical portion of the valve stem into the forming metering chamber andas the valve stem is further pushed in the upper surface (29) of theconical portion forms a face seal with the inner seal (16), therebysealing off the metering chamber. As the valve stem is yet furtherdisplaced inwardly, formulation is allowed to pass from the meteringchamber through side holes (19) in the valve stem and through a stemoutlet (24) in the valve stem, and subsequently out to the patienttypically via an actuator nozzle (7, not shown).

FIG. 4 shows a commercial metered dose valve supplied by Bespak, BergenWay, King's Lynn, Norfolk, PE30 2JJ, UK under the trade designationBK357, in its resting position.

The valve includes a secondary valve body (20) in the form of a springcage with two slots (21) and an opening at the top (21′) allowingcommunication between the formulation chamber (not shown) and apre-metering chamber (22). The valve also includes a valve stem (14),made of two components (14 a, 14 b), which is biased outwardly by acompression spring (15) and passes through a metering chamber (12)defined in part by a primary valve body (13). The valve stem is insliding sealing engagement with an inner seal (16) and an outerdiaphragm seal (17). Aerosol formulation can pass from the pre-meteringchamber (22) into the metering chamber (12) via side holes (33 a, 33 b)in the upper portion (14 a) of the stem (14). Similar to the valve shownin FIG. 1, to actuate (fire) the valve, the valve stem (14) is pushedinwardly relative to the container, allowing a metered dose offormulation to pass from the metering chamber through a side hole (19)in the valve stem and through a stem outlet (24) and then typicallythrough an actuator nozzle (7, not shown) out to the patient.

FIG. 5 shows a commercial metered dose valve supplied by Valois SAS,Pharmaceutical Division, Route des Falaises, 27100 le Vaudreuil, Franceunder the trade designation RCS, in its resting position. The valveincludes a secondary valve body (20) in the form of a spring cage withthree slots (21, two visible) allowing communication between theformulation chamber (not shown) and a pre-metering chamber (22). Thevalve also include a valve stem (14), made of two components (14 a, 14b), which is biased outwardly by a compression spring (15) and passesthrough a metering chamber (12) defined in part by a primary valve body(13). The valve stem is in sliding sealing engagement with an inner seal(16) and an outer diaphragm seal (17). Aerosol formulation can pass fromthe pre-metering chamber (22) into the metering chamber through a sidehole (33) and an internal channel (34) provided in the upper portion (14a) of the valve stem. Similar to the valve shown in FIG. 1, to actuate(fire) the valve, the valve stem (14) is pushed inwardly relative to thecontainer, allowing formulation to pass from the metering chamberthrough a side hole (19) in the valve stem and through a stem outlet(24) and then typically through an actuator nozzle (7, not shown) out tothe patient.

With the exception of the elastomeric seals used in metered dose valves,typically the components of such valves are made of metal (e.g.stainless steel, aluminum or aluminum alloy) or plastic. For examplecompression springs are generally made of a metal, in particularstainless steel as the conventional material. Compression springs mayalso be made of aluminum or aluminum alloy. Valve stems and valve bodiesare generally made of metal and/or plastic; as a metal conventionallystainless steel is used (other metals that may be used include aluminum,aluminum alloy and titanium) and as plastics conventionally polybutyleneterephthalate (PBT) and/or acetal are used (other polymers that may beused include polyetheretherketones, nylon, other polyesters (such astetrabutylene terephthalate), polycarbonates and polyethylene).

Favorably at least a portion of a surface, more favorably the entiresurface, of a component or components of a medicinal inhalation device(e.g. aerosol containers, actuators, ferrules, valve bodies, valve stemsor compression springs of metered dose inhalers or powder containers ofdry powder inhalers) which is or will come in contact with a medicamentor a medicinal formulation during storage or delivery from the medicinalinhalation device are treated according to methods described herein.Most favorably the entire surface of the component, including anysurface or surfaces (if present) that do not or will not come in contactwith a medicament or a medicinal formulation during storage or deliveryfrom the device, are treated according to methods described herein.Alternatively or additionally, favorably at least a portion of asurface, more favorably the entire surface, of a component or componentsof a medicinal inhalation device, which either come in contact with amovable component or are movable during storage or delivery from themedicinal inhalation device are treated according to methods describedherein. Examples of such components for metered dose inhalers includee.g. valve bodies, valve stems or compression springs of metered dosevalves.

In particular a component of a medicinal inhalation device in accordancewith the present invention or made according to methods in accordancewith the present invention is a component of a metered dose inhaler.Said component may be selected from the group consisting of aerosolcontainer, an actuator, a ferrule, a valve body (e.g. a primary and/or asecondary valve body), a valve stem and a compression spring.Alternatively a component of a medicinal inhalation device in accordancewith the present invention or made according to methods in accordancewith the present invention is a component of a dry powder inhaler. Saidcomponent may be selected from the group consisting of a component thatdefines at least in part a powder container (e.g. a multidose reservoircontainer or single dose blister or capsule), an component used to opena sealed powder container (e.g. piercer to open single dose blisters orcapsules), a component that defines at least in part a deagglomerationchamber, a component of a deaglomeration system, a component thatdefines at least in part a flow channel, a dose-transporting component(e.g. a dosing rod, dosing wheel or dosing cylinder with a recessdimensioned to accommodate a single dose of powder trapped between saidcomponent and a housing in which it moves to transport the dose), acomponent that defines at least in part a mixing chamber, a componentthat defines at least in part an actuation chamber (e.g. a holdingchamber where a dose is dispensed prior to inhalation), a mouthpiece anda nosepiece.

Embodiments in accordance with certain aspects of the present inventioninclude forming a non-metal coating on at least a portion of a surfaceof a medicinal inhalation device or a component of a medicinalinhalation device (e.g. an aerosol container of a metered dose inhaler,a metered dose valve or a component thereof, or a powder container of adry powder inhaler), said coating having at least one functional group,where the at least one functional group is capable of forming a covalentbond with the at least one functional group of the at least partiallyfluorinated compound.

The term “at least one functional group” as used herein is to begenerally understood to include as a preferred embodiment “a pluralityof functional groups”.

The at least one functional group of the non-metal coating desirablyincludes an active hydrogen. The at least one functional group isfavorably a hydroxyl group (—OH), a thiol group (—SH), an amine group(—NH— or —NH₂), a carboxyl group (—COOH), an amide group (—CONH— or—CONH₂) or a mixture of such groups; more favorably a hydroxyl group, acarboxyl group or a mixture of such groups; and most favorably ahydroxyl group.

Favorably the aforesaid forming a non-metal coating includes forming acoating comprising silicon, oxygen, and hydrogen, more favorably anon-metal coating comprising carbon, silicon, oxygen and hydrogen.

Non-metal coatings described herein may be formed through a variety ofknown coating techniques. However it has been found that the applicationof such coatings through plasma deposition is desirable, more desirablythrough plasma deposition under conditions of ion bombardment.

In particular non-metal coatings (more particularly coatings comprisingsilicon, oxygen and hydrogen, and most particularly coatings comprisingsilicon, oxygen, hydrogen and carbon) may be desirably provided byplasma polymerization of an appropriate monomer or monomers, optionallyin the presence of an appropriate assist gas, such as oxygen, usingconventional conditions used in e.g. microwave, inductively coupled, DCand RF (radio frequency) plasma deposition, where polymerized speciesformed in the plasma deposit on the substrate to provide a polymercoating on the surface(s) of the substrate.

More desirably non-metal coatings (more particularly coatings comprisingsilicon, oxygen and hydrogen, and most particularly coatings comprisingcarbon, silicon, oxygen, and hydrogen) are provided by plasma depositionunder conditions of ion bombardment. Here plasma deposition is carriedout in such a way that an ion sheath is formed upon generation of theplasma (plasma formed from an appropriate source compound or compounds,optionally in the presence of an appropriate assist gas, such as oxygen)and where the substrate, whose surface is or surfaces are to be coated,is positioned within the plasma chamber so that during plasma depositionthe substrate is within the ion sheath. An explanation of the formationof ion sheaths can be found in Brian Chapman, Glow Discharge Processes,153 (John Wily & Sons, New York 1980). For RF-plasma deposition, thiscan be generally accomplished through the use of a RF-powered electrodeand locating the substrate to be coated in proximity to the RF-poweredelectrode. For microwave plasma deposition and inductively coupledplasma deposition, this can be accomplished by providing the microwaveor inductively coupled plasma system, respectively, with an electrode,biasing (generally negatively biasing) this electrode and locating thesubstrate in proximity to said biased electrode. For DC plasmadeposition, this can be accomplished by locating the substrate inproximity to the cathode or negatively biased electrode (e.g. forproviding thin coatings of 10 nm or less). In this manner plasmadeposition occurs under conditions of ion bombardment. Moreoverpolymerized species formed in the plasma are subjected to ionbombardment, and are thus among other things fragmented, beforedepositing and/or upon deposition on the substrate allowing theprovision of an advantageous, dense, random, covalent system on thesurface(s) of the substrate. Such amorphous covalent systems (inparticular such systems comprising silicon, oxygen and hydrogen, andmore particularly further comprising carbon), show excellent adhesion(through e.g. covalent bonding) to many substrate materials, includingmetals, polymers, glass and ceramics. Such covalent amorphous systemsprovide “sharp” coatings e.g. on complex-formed components such as valvestems or compression springs. Such covalent amorphous systems (inparticular such systems comprising silicon, oxygen and hydrogen, andmore particularly further comprising carbon) are desirable in that theyare typically transparent or translucent. Furthermore, such amorphouscovalent systems show advantageously high atomic packing densities,typically in a range from about 0.20 to about 0.28 (in particular fromabout 0.22 to about 026) gram atom number density in units of gram atomsper cubic centimeter. Polymeric coatings (e.g. plasma polymer coatings)generally have gram atom number densities around 0.18. Such high atomicpacking densities allow the provision of coatings having a minimum ofporosity, excellent resistance to diffusion to liquid or gaseousmaterials, and superb, “diamond-like” hardness. Micro-hardness of suchcoatings, as determined using a nanoidenter, is generally, favorably atleast 1 GPa, more favorably at least 2 GPa. Such coatings alsoadvantageously have a low coefficient of friction/surface energy. Suchcoatings further comprising carbon, generally termed here as“diamond-like glass” show desirous flexibility together withdiamond-like hardness, allowing for desirable long-term durability, inparticular advantageous long-term durability of said coatings on movablecomponents (e.g. compression springs) or on components coming intocontact with other components due to movement (e.g. valve stems, valvebodies). Micro-elastic-modulus of such coatings, as determined using ananoidenter, is generally, favorably at least 11 GPa, more favorably atleast 13 GPa. Due to the desirable properties of the aforesaid describedcoatings, they are particularly advantageous for use as coatings inmedicinal inhalation devices or components thereof either alone or as acoating onto which a composition comprising an at least partiallyfluorinated compound comprising at least one functional group isapplied. In regard to the latter, again due to desirable high atomicpacking densities such non-metal coatings allow for the provision of adense distribution and high number of functional groups, such asfunctional groups having an active hydrogen (e.g. hydroxyl groups (—OH)and/or carboxyl groups (—COOH), in particular hydroxyl groups) forsubsequent bonding upon application of said composition comprising atleast partially fluorinated compound comprising an at least onefunctional group.

Coatings provided by plasma deposition under conditions of ionbombardment and comprising silicon, oxygen and hydrogen desirably have asilicon to oxygen ratio less than two.

Diamond-like glass coatings (e.g. coatings provided by plasma depositionunder conditions of ion bombardment and comprising carbon, silicon,oxygen and hydrogen) favorably contain on a hydrogen free basis at leastabout 20 atomic percent carbon and at least about 30 atomic percent ofsilicon+oxygen, more favorably at least about 25 atomic percent carbon,about 15 to about 50 atomic percent of silicon and about 15 to about 50atomic percent oxygen, even more favorably about 30 to about 60 atomicpercent carbon, about 20 to about 45 atomic percent of silicon and about20 to about 45 atomic percent oxygen, yet even more favorably about 30to about 50 atomic percent carbon, about 25 to about 35 atomic percentof silicon and about 25 to about 45 atomic percent oxygen, and mostfavorably about 30 to about 36 atomic percent carbon, about 26 to about32 atomic percent of silicon and about 35 to about 41 atomic percentoxygen. Diamond-like glass coatings desirably have a silicon to oxygenratio less than two. “Hydrogen free basis” refers to the atomiccomposition of a material as established by a method such as ElectronSpectroscopy for Chemical Analysis (ESCA) which does not detect hydrogeneven if large amounts are present in the coating. The combination offairly high amounts of silicon and oxygen with significant amountscarbon makes diamond-like glass coatings flexible (unlike glass oramorphous carbon coatings such as diamond-like carbon coatings). Alsodue to said combination diamond-like glass coatings have relatively lowintrinsic stress and thus excellent long-term adhesion and durability(unlike diamond-like carbon coatings which have a tendency to flake offdue to relatively high intrinsic stress within the coating). Thusdiamond like glass coatings are particularly advantageous as coatings ona surface or surfaces of medicinal inhalation device components whichundergo movement in itself (e.g. a compression spring of a metered dosevalve) or movement in conjunction with or relative to other components(e.g. a valve stem of a metered dose valve). Diamond-like glass coatingsas well as methods of making diamond-like glass and apparatus fordepositing diamond-like glass are described in U.S. Pat. No. 6,696,157(David et al), the contents of which is incorporated here in itsentirety.

It is to be recognized that plasma deposition under conditions of ionbombardment is distinct from plasma polymerization. Moreover in plasmapolymerization techniques, plasma deposition is carried out in such amanner that no ion sheath is formed (e.g. using conventional microwaveor inductively coupled plasma systems) or the substrate to be coatedwith the polymer is positioned outside of any ion sheath, if at allformed. For example, in regard to the RF-plasma systems using aRF-powered electrode, for plasma polymerization, i.e. deposition of thepolymer on the substrate, the substrate is located in proximity to thegrounded electrode or placed at a floating potential (i.e. electricallyisolated and located outside of any ion sheath formed during RF-plasmadeposition).

The term “plasma deposition” as used herein, unless otherwise specified,will be understood to include inter alia plasma polymerization as wellas plasma deposition under conditions of ion bombardment, where in eachcase plasma deposition under conditions of ion bombardment is understoodto be preferred. Similarly the term “plasma deposited” as used herein,unless otherwise specified, will be understood to include inter aliaplasma polymerized as well as plasma deposited under ion bombardment,where in each case plasma deposited under ion bombardment is understoodto be preferred.

Forming a non-metal coating as described herein by plasma deposition canbe carried out in a suitable reaction chamber having acapacitively-coupled system with at least one electrode powered by an RF(radio frequency) source and at least one grounded electrode, such asthose described in U.S. Pat. Nos. 6,696,157 (David et al.) and 6,878,419(David et al.). FIG. 6 illustrates an exemplary apparatus (200) suitablefor the plasma deposition, in particular plasma deposition underconditions of ion bombardment, showing a grounded chamber (120) (alsoacting here as a grounded electrode) from which air is removed by apumping stack (not shown). The gas or gases to form the plasma aregenerally injected radially inwardly through the reactor wall to an exitpumping port in the center of the chamber. Substrate (140), typically amedicinal inhalation device component per se or alternatively awork-piece from which such a component may be subsequently formed orworked, is favorably positioned proximate RF-powered electrode (160).Electrode (160) is insulated from chamber (120) by apolytetrafluoroethylene support (180). FIG. 7 illustrates anotherexemplary apparatus (200) for the plasma deposition, in particularplasma deposition under conditions of ion bombardment, where a substrateor (as shown in FIG. 7) a plurality of substrates (140) (again suchsubstrate(s) being typically medicinal inhalation device component(s)per se or alternatively a work-piece(s) from which such a component maybe subsequently formed or worked) are tumbled during deposition, suchtumbling favorably allowing for uniform deposition on the surfaces ofthe substrate(s). Here the chamber (120) is a tube, in particular aquartz tube, the ends of which are sealed with flanges (not shown), inparticular aluminum flanges. Each end flange is typically provided witha port, a port at one end being connected to a pumping stack (not shown)and a port at the other end being connected to gas supply system (notshown). The ports together with the connecting-system are favorablyconfigured and arranged to allow for rotation of the tube and thus thechamber during plasma deposition. Air is typically removed from thechamber after loading by the pumping stack through the exit pumpingport, and the gas or gases to form the plasma are generally injectedthrough the inlet gas port at the other end, said gas or gases passingthen through the chamber towards the exit pumping port. RF-powderedelectrode (160) is advantageously configured as an arc conforming to thecurvature of the tube and is positioned just underneath the tube butseparated from the tube by a narrow gap. The chamber and RF-poweredelectrode are favorably housed inside with a housing (130), inparticular a housing made of a perforated metal, that serves as agrounded counter electrode. Similar to the system shown in FIG. 6, poweris typically provided by a RF power supply (170) through a matchingnetwork (175). During treatment with such a system, the chamber (120) isadvantageously rotated so the substrate(s) (140) to be coated tumble;tumbling can be desirably facilitated through the inclusion of baffles(125) within the tube. Through an appropriate degree of substrateloading together with tumbling at an appropriate rate during plasmadeposition, the substrate(s) to be coated will be found with the lowerportion of the tube, and thus favorably positioned in proximity of theRF-powered electrode (160) so that the substrate(s) will be locatedwithin the ion sheath.

Before plasma deposition, it is desirable to expose the substrate to anoxygen plasma or alternatively an argon plasma, more desirably oxygenplasma. It is most desirable to expose the substrate to an oxygen plasmaunder conditions of ion bombardment (i.e. generating an ion sheath andhaving the substrate located within the ion sheath during said oxygenplasma treatment). Typically for this pre-treatment, pressures in thechamber are maintained between 1.3 Pa (10 mTorr) and 27 Pa (200 mTorr).Plasma is generated with RF power levels of between 500 W and 3000 W.

A solvent washing step with an organic solvent such as acetone orethanol may also be included prior to the exposure to an oxygen or argonplasma as described above.

Referring to the exemplary apparatus shown in FIG. 6, for plasmadeposition under ion bombardment conditions the substrate is located inproximity of the RF-powered electrode (as schematically depicted in FIG.6) in the chamber so that the substrate will be within the ion sheath.For plasma polymerization, the substrate to be coated would be placed inthe chamber at a floating potential with the substrate being locatedsuch that it would not be within the ion sheath. Alternatively forplasma polymerization, an alternative system may be used which isprovided with an additional grounded electrode (rather than having thechamber act as the grounded electrode) and the substrate to be coatedwould be then located in the proximity of the grounded electrode.

The chamber is typically evacuated to the extent necessary to remove airand any impurities. This may be accomplished by vacuum pumps at apumping stack connected to the chamber. A source gas is introduced intothe chamber at a desired flow rate, which depends on the size of thereactor, the surface area of the electrodes, and the surface area of thesubstrate. The gas is typically and desirably oxygen.

For the provision of a plasma deposited coating comprising silicon,oxygen and hydrogen or a plasma deposited coating comprising carbon,silicon, oxygen and hydrogen, during plasma deposition, the gas furthercomprises an appropriate organosilicon and/or a silicon hydridecompound, and the flow rates are sufficient to establish a suitablepressure at which to carry out plasma deposition, typically 0.13 Pa to130 Pa (0.001 Torr to 1.0 Ton). For a cylindrical reactor that has aninner diameter of approximately 55 cm and a height of approximately 20cm, the flow rates are typically from about 50 to about 500 standardcubic centimeters per minute (sccm). At the pressures and temperatures(less than about 50° C.) of the plasma deposition, the gas remains inthe vapor form. An RF electric field is applied to the poweredelectrode, ionizing the gas and establishing a plasma. In theRF-generated plasma, energy is coupled into the plasma throughelectrons. The plasma acts as the charge carrier between the electrodes.The plasma can fill the entire reaction chamber and is typically visibleas a colored cloud.

The plasma also forms an ion sheath proximate at least to the RF-poweredelectrode. The ion sheath typically appears as a darker area around theelectrode. The depth of the ion sheath normally ranges from about 1 mmto about 50 mm and depends on factors such as the type and concentrationof gas used, pressure in the chamber, the spacing between theelectrodes, and relative size of the electrodes. For example, reducedpressures will increase the size of the ion sheath. When the electrodesare different sizes, a larger, stronger ion sheath will form around thesmaller electrode. Generally, the larger the difference in electrodesize, the larger the difference in the size of the ion sheaths, andincreasing the voltage across the ion sheath will increase ionbombardment energy.

In preferred embodiments in which a substrate, whose surface is orsurfaces are to be coated, is located within an ion sheath, ionsaccelerating toward the electrode bombard the species being depositedfrom the plasma onto the substrate and thus the substrate is exposed tothe ion bombarded species being deposited from the plasma. The resultingreactive species within the plasma react on the surface of thesubstrate, forming a coating, the composition of which is controlled bythe composition of the gas being ionized in the plasma. The speciesforming the coating are advantageously attached to the surface of thesubstrate by covalent bonds, and therefore the coating is advantageouslycovalently bonded to the substrate.

For favorable embodiments including formation of a coating comprisingsilicon, oxygen, and hydrogen or more favorably a coating comprisingcarbon, silicon, oxygen and hydrogen, plasma deposition comprisesionizing a gas comprising at least one of an organosilicon or a siliconhydride compound. Typically the silicon of the at least one of anorganosilicon or a silicon hydride compound is present in an amount ofat least about 5 atomic percent of the gas mixture. If a reactive gas(such as oxygen) and/or an inert gas (such as argon) are mixed alongwith the organosilicon and/or silicon hydride source compound, theatomic percent of silicon in the gas mixture is calculated based on thevolumetric (or molar) flow rates of the component gases in the mixture.For embodiments including formation of a coating comprising carbon,silicon, oxygen and hydrogen, the gas desirably comprise anorganosilicon. In particular the organosilicon comprises at least one oftrimethylsilane, triethylsilane, trimethoxysilane, triethoxysilane,tetramethylsilane, tetraethylsilane, tetramethoxysilane,tetraethoxysilane, hexamethylcyclotrisiloxane,tetramethylcyclotetrasiloxane, tetraethylcyclotetrasiloxane,octamethylcyclotetrasiloxane, hexamethyldisiloxane, andbistrimethylsilylmethane. More particularly the organosilicon comprisesat least one of trimethylsilane, triethylsilane, tetramethylsilane,tetraethylsilane, and bistrimethylsilylmethane; and most particularlythe organosilicon comprises tetramethylsilane. In addition to oralternatively (e.g. for provision of coatings comprising silicon, oxygenand hydrogen having less than 20 atomic percent of carbon (onhydrogen-free basis) or no carbon), the gas may comprise a siliconhydride. The silicon hydride may comprise SiH₄ (silicon tetrahydride)and/or Si₂H₆ (disilane), in particular SiH₄ (silicon tetrahydride).

Preferably the gas further comprises oxygen.

The gas may further comprise an additional gas or gases. Each additionalgas can be added separately or in combination with each other. The gasmay further comprise argon and/or hydrogen, in particular for plasmadeposition under ion bombardment conditions. The application of argon(normally is not incorporated into the deposited coating) enhances ionbombardment, while the application of hydrogen promotes the formation ofhigh packing density as well as provides an additional source ofhydrogen. Optionally the gas may further comprise ammonia and/ornitrogen. However for certain preferred embodiments, described in moredetailed infra, in which a composition comprising an at least partiallyfluorinated compound comprising at least one silane group will beapplied, it is desirable not to use ammonia and nitrogen gas, nor asulfur containing gas. Moreover, for certain preferred embodiments inwhich a composition comprising an at least partially fluorinatedcompound comprising at least one silane group will be applied, it isdesirable that the non-metal coating as described herein issubstantially free or free of amine groups and substantially free orfree of amido groups as well as substantially free or free of thiolgroups so as to minimize or avoid formation of silicon-nitrogen orsilicon-sulfur bonds, said bonds having been determined to beundesirable in terms of durability and/or robustness of the coatingsystem over the life of medicinal inhalation devices. Accordingly inpreferred embodiments, the non-metal coating is advantageouslysubstantially free of nitrogen (e.g. at most about 5 atomic percent ofnitrogen (on a hydrogen free basis)), in particular free of nitrogen.Also in preferred embodiments, the non-metal coating is advantageouslysubstantially free of sulfur (e.g. at most about 1 atomic percent ofsulfur (on a hydrogen free basis)), in particular free of sulfur.Optionally the gas may further comprise a source of fluorine e.g. carbontetrafluoride. However, it is preferred (in general and moreparticularly for plasma deposition under ion bombardment conditions) notto include fluorine into the non-metal coating. The inclusion offluorine has been determined to be generally undesirable in terms ofstructural integrity of non-metal coating (in particular adhesion of thenon-metal coating to the substrate surface as well as overall durabilityof the non-metal coating). Also for those embodiments in which acomposition comprising an at least partially fluorinated compoundcomprising at least one functional group is applied onto the non-metalcoating the inclusion of fluorine is undesirable in terms of adhesion ofthe applied fluorine-containing composition onto the non-metal coating.Thus in certain aspects of the present invention and in preferredembodiments of other aspects of the present invention, the non-metalcoating is advantageously substantially free of fluorine (e.g. at mostabout 1 atomic percent of fluorine (on a hydrogen free basis)), inparticular free of fluorine.

Plasma deposition of the non-metal coating typically occurs at a rateranging from about 1 to about 100 nm/second. The rate will depend onconditions including pressure, power, concentration of gas, types ofgases, relative size of the electrodes, and so on. In general, thedeposition rate increases with increasing power, pressure, andconcentration of gas, although the rate can approach an upper limit.

Desirably plasma deposition of the non-metal coating is carried out fora period of time such that the coating has a thickness in the range fromabout 5 nm to about 5000 nm. Generally within this range it is favorableto provide coatings having a thickness of at least about 10 nm, morefavorably at least about 50 nm, and most favorably at least about 100nm. Also within the aforesaid ranges generally it is favorable toprovide coatings having a thickness less than about 1000 nm, morefavorably at most about 950 nm, even more favorably at most about 800nm, yet even more favorably at most about 675 nm and most favorably atmost about 550 nm.

After the non-metal coating is formed (in particular a non-metal coatingcomprising silicon, oxygen and hydrogen, more particularly a coatingcomprising carbon, silicon, oxygen, hydrogen formed by plasmadeposition) the surface of the non-metal coating is favorably exposed toan oxygen plasma, more favorably exposed to an oxygen plasma under ionbombardment conditions (for example in order to form or to formadditional silanol groups on the surface of the non-metal coating). Sucha treatment is particularly advantageous for embodiments in which acomposition comprising an at least partially fluorinated compoundcomprising at least one functional group will be applied. For suchtreatment, pressures in the plasma chamber are typically maintainedbetween 1.3 Pa (10 mTorr) and 27 Pa (200 mTorr), and oxygen plasma isgenerated with RF power levels of between about 50 W and about 3000 W.

Embodiments according to certain aspects of the present inventioninclude applying to at least a portion of a surface of the non-metalcoating a composition comprising an at least partially fluorinatedcompound comprising at least one functional group, and allowing at leastone functional group of the at least partially fluorinated compound toreact with at least one functional group of the non-metal coating toform a covalent bond. Preferably said composition is applied to theentire surface of the non-metal coating.

As mentioned previously, prior to applying the composition comprising anat least partially fluorinated compound comprising at least onefunctional group, the non-metal coating is desirably exposed to anoxygen plasma, more desirably exposed to an oxygen plasma under ionbombardment conditions. Alternatively, the non-metal coating may befavorably exposed to a corona treatment prior to applying thecomposition comprising the at least partially fluorinated compoundcomprising at least one functional group.

Desirably the at least partially fluorinated compound includes apolyfluoropolyether segment, preferably a perfluorinatedpolyfluoropolyether segment, for enhanced surface properties as well asenhanced coating efficiency and structural integrity. The use ofpolyfluoropolyether segments including perfluorinated repeating unitsincluding short chains of carbon, where desirably the number of carbonatoms in sequence is at most 6, more desirably at most 4, even moredesirably at most 3, and most desirably at most 2, facilitatesdurability/flexibility of the applied fluorine-containing coating aswell as minimizing a potential of bioaccumulation of perfluorinatedmoieties.

Desirably the at least one functional group of the at least partiallyfluorinated compound includes a hydrolysable group (e.g. hydrolysable inthe presence of water, optionally under acidic or basic conditionsproducing groups capable of undergoing a condensation reaction (forexample silanol groups)).

Desirably the at least one functional group of the at least partiallyfluorinated compound is a silane group.

Favorably the silane group includes at least one hydrolysable group,more favorably at least two hydrolysable groups, and most favorablythree hydrolysable groups. The hydrolysable groups may be the same ordifferent.

Desirably a hydrolysable group is a group selected from the groupconsisting of hydrogen, halogen, alkoxy, acyloxy, aryloxy, andpolyalkyleneoxy, more desirably a group selected from the groupconsisting of alkoxy, acyloxy, aryloxy, and polyalkyleneoxy, even moredesirably a group selected from the group consisting of alkoxy, acyloxyand aryloxy, and most desirably an alkoxy group (e.g. OR' wherein eachR′ is independently a C₁₋₆ alkyl, in particular a C₁₋₄ alkyl).

Desirably the at least partially fluorinated compound comprising atleast one functional group is a polyfluoropolyether silane, moredesirably a multifunctional polyfluoropolyether silane, and mostdesirably a difunctional polyfluoropolyethersilane.

The term “multifunctional polyfluoropolyether silane” as used herein isgenerally understood to mean a multivalent polyfluoropolyether segmentfunctionalized with a multiple of functional silane groups, and the term“difunctional polyfluoropolyether silane” as used herein is generallyunderstood to mean a divalent polyfluoropolyether segment functionalizedwith a multiple of functional silane groups (in particular two to fourfunctional silane groups, more particular two functional silane groups).

It has been found that the use of a multifunctional polyfluoropolyethersilane, in particular a difunctional polyfluorpolyether silane, allowsfor high application efficiency and coverage as well as extensivebonding (covalent bonding) to the non-metal coating and cross-linkingwithin the fluorine containing coating itself facilitating structuralintegrity of the applied fluorine-containing coating.

For enhanced stability and/or resistance to attack (e.g. by ethanol,drug, and/or other potential components of medicinal inhalationformulations) desirably polyfluoropolyether segment(s) is (are) notlinked to silane group(s) via a functionality that includes anitrogen-silicon bond or sulfur-silicon bond. In particular, forenhanced stability and resistance of the applied fluorine-containingcoating to attack, it is desirable that polyfluoropolyether segment(s)is (are) linked to silane group(s) via a functionality that include acarbon-silicon bond, more particularly via a —C(R)₂—Si functionalitywhere R is independently hydrogen or a C₁₋₄ alkyl group (preferablyhydrogen), and most particular, via a —(C(R)₂)_(k)—C(R)₂—Sifunctionality where k is at least 2 (preferably 2 to about 25, morepreferably 2 to about 15, most preferably 2 to about 10). The inclusionof —(C(R)₂)_(k)— where k is at least 2 advantageously, additionallyprovides flexural strength

Favorably, the at least partially fluorinated compound comprising atleast one silane group is a polyfluoropolyether silane of the FormulaIa:

R_(f)[Q-[C(R)₂—Si(Y)_(3-x)(R^(1a))_(x)]_(y)]_(z)  Ia

-   -   wherein:        -   R_(f) is a monovalent or multivalent polyfluoropolyether            segment;        -   Q is an organic divalent or trivalent linking group;        -   each R is independently hydrogen or a C₁₋₄ alkyl group;        -   each Y is independently a hydrolysable group;        -   R^(1a) is a C₁₋₈ alkyl or phenyl group;        -   x is 0 or 1 or 2;        -   y is 1 or 2; and        -   z is 1, 2, 3, or 4.

Application of polyfluoropolyether silanes in accordance with Formula Iafavorably allows the provision of medicinal inhalation devices orcomponents thereof comprising a non-metal coating on at least a portionof surface of the device or component, as applicable, and apolyfluoropolyether-containing coating bonded to the non-metal coating,wherein the polyfluoropolyether-containing coating comprisespolyfluoropolyether silane entities of the following Formula Ib:

R_(f)[Q-[C(R)₂—Si(O—)_(3-x)(R^(1a))_(x)]_(y)]_(z)  Ib

which shares at least one covalent bond with non-metal coating; and

-   -   wherein:        -   R_(f) is a monovalent or multivalent polyfluoropolyether            segment;        -   Q is an organic divalent or trivalent linking group;        -   each R is independently hydrogen or a C₁₋₄ alkyl group;        -   R^(1a) is a C₁₋₈ alkyl or phenyl group;        -   x is 0 or 1 or 2;        -   y is 1 or 2; and        -   z is 1, 2, 3, or 4.

Advantageously the at least one covalent bond shared with the non-metalcoating is a bond to an oxygen atom in Si(O—)_(3-x). Favorably suchpolyfluoropolyether-containing coatings are typically transparent ortranslucent.

The monovalent or multivalent polyfluoropolyether segment, R_(f),includes linear, branched, and/or cyclic structures, that may besaturated or unsaturated, and includes two or more in-chain oxygenatoms. R_(f) is preferably a perfluorinated group (i.e., all C—H bondsare replaced by C—F bonds). However, hydrogen atoms may be presentinstead of fluorine atoms provided that not more than one atom ofhydrogen is present for every two carbon atoms. When hydrogen atoms arepresent, preferably, R_(f) includes at least one perfluoromethyl group.

For certain embodiments, the monovalent or multivalentpolyfluoropolyether segment, R_(f), comprises perfluorinated repeatingunits selected from the group consisting of —(C_(n)F_(2n))—,—(C_(n)F_(2n)O)—, —(CF(Z))—, —(CF(Z)O)—, —(CF(Z)C_(n)F_(2n)O)—,—(C_(n)F_(2n)CF(Z)O)—, —(CF₂CF(Z)O)—, and combinations thereof; whereinn is an integer from 1 to 6; Z is a perfluoroalkyl group, anoxygen-containing perfluoroalkyl group, a perfluoroalkoxy group, or anoxygen-substituted perfluoroalkoxy group, each of which can be linear,branched, or cyclic, and have 1 to 5 carbon atoms and up to 4 oxygenatoms when oxygen-containing or oxygen-substituted. For units comprisingZ it is desirable that the total number of carbon atoms in sequence perunit is at most 6 (more desirably at most 4, and most desirably at most3). Being oligomeric or polymeric in nature, these compounds exist asmixtures and are suitable for use as such. The perfluorinated repeatingunits may be arranged randomly, in blocks, or in an alternatingsequence. Favorably, the polyfluoropolyether segment comprisesperfluorinated repeating units selected from the group consisting of—(C_(n)F_(2n)O)—, —(CF(Z)O)—, —(CF(Z)C_(n)F_(2n)O)—,—(C_(n)F_(2n)CF(Z)O)—, —(CF₂CF(Z)O)—, and combinations thereof; and morefavorably perfluorinated repeating units selected from the groupconsisting of —(C_(n)F_(2n)O)—, —(CF(Z)O)—, and combinations thereof.For certain of these embodiments, n is an integer from 1 to 4; or 1 to3; or 1 or 2. For certain of these embodiments, Z is a —CF₃ group.

For certain embodiments, including any one of the above embodiments,R_(f) is monovalent, and z is 1. For certain of these embodiments, R_(f)is terminated with a group selected from the group consisting ofC_(n)F_(2n+1)—, C_(n)F_(2n+1)O—, and X′C_(n)F_(2n)O— wherein X′ is ahydrogen. For certain of these embodiments, the terminal group isC_(n)F_(2n+1)— or C_(n)F_(2n+1)O— wherein n is an integer from 1 to 6 or1 to 3. For certain of these embodiments, the approximate averagestructure of R_(f) is C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—,CF₃O(C₂F₄O)_(p)CF₂—, C₃F₇O(CF(CF₃)CF₂O)_(p)CF₂CF₂—,C₃F₇O(CF₂CF₂CF₂O)_(p)CF₂CF₂—, or C₃F₇O(CF₂ CF₂CF₂O)_(p)CF(CF₃)—, orCF₃O(CF₂CF(CF₃)O)_(p)(CF₂O)X— (wherein X is CF₂—, C₂F₄—, C₃F₆—, C₄F₈—)wherein the average value of p is 3 to 50.

For enhanced application efficiency and coverage as well as extensivebonding to non-metal coating and inter-linking within thefluorine-containing coating itself, thus facilitating a high structuralintegrity of applied fluorine-containing coating, R_(f) is preferablymultivalent and z is 2, 3 or 4, more preferably R_(f) is divalent, and zis 2. For certain of these embodiments, the approximate averagestructure of R_(f) is selected from the group consisting of—CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂—, —CF₂O(C₂F₄O)_(p)CF₂—,—CF(CF₃)O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, —(CF₂)₃O(C₄F₈O)_(p)(CF₂)₃—,—CF(CF₃)—(OCF₂CF(CF₃))_(p)O—C_(t)F_(2t)—O(CF(CF₃)CF₂O)_(p)CF(CF₃)—(wherein t is 2 to 4), and wherein m is 1 to 50, and p is 3 to 40. Forcertain of these embodiments, R_(f) is selected from the groupconsisting of —CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂—, —CF₂O(C₂F₄O)_(p)CF₂—, and—CF(CF₃)—(OCF₂CF(CF₃))_(p)O—(C_(t)F_(2t))—O(CF(CF₃)CF₂O)_(p)CF(CF₃)—,and wherein t is 2, 3 or 4, and the average value of m+p or p+p or p isfrom about 4 to about 24.

The above structures are approximate average structures where p and mdesignate the number of randomly distributed perfluorinated repeatingunits. Further, polyfluoro-polyether silanes, such as those describedabove, also typically include a distribution of oligomers and/orpolymers, so p and/or m may be non-integral and where the number is theapproximate average is over this distribution.

The organic divalent or trivalent linking group, Q, can include linear,branched, or cyclic structures that may be saturated or unsaturated. Theorganic divalent or trivalent linking group, Q, optionally contains oneor more heteroatoms selected from the group consisting of sulfur,oxygen, and nitrogen, and/or optionally contains one or more functionalgroups selected from the group consisting of esters, amides,sulfonamides, carbonyl, carbonates, ureylenes, and carbamates. Again forflexural strength Q favorably includes a segment with not less than 2carbon atoms, said segment of Q being directly bonded to the —C(R)₂—group of the silane-containing moiety (i.e. for Formula Ia—C(R)₂—Si(Y)_(3-x)(R^(1a))_(x) and for Formula Ib—C(R)₂—Si(O—)_(3-x)(R^(1a))_(x)). For such embodiments generally Qincludes not more than about 25 carbon atoms. Q is preferablysubstantially stable against hydrolysis and other chemicaltransformations, such as nucleophilic attack. When more than one Qgroups are present, the Q groups can be the same or different.

For certain embodiments, including any one of the above embodiments, Qincludes organic linking groups such as —C(O)N(R)—(CH₂)_(k)—,—S(O)₂N(R)—(CH₂)_(k)—, —(CH₂)_(k)—, —CH₂O—(CH₂)_(k)—, —C(O)S—(CH₂)_(k)—,—CH₂OC(O)N(R)—(CH₂)_(k)—, and

wherein R is hydrogen or C₁₋₄ alkyl, and k is 2 to about 25. For certainof these embodiments, k is 2 to about 15 or 2 to about 10.

Favorably Q is a divalent linking group, and y is 1. In particular, Q isfavorably a saturated or unsaturated hydrocarbon group including 1 toabout 15 carbon atoms and optionally containing 1 to 4 heteroatomsand/or 1 to 4 functional groups. For certain of these embodiments, Q isa linear hydrocarbon containing 1 to about 10 carbon atoms, optionallycontaining 1 to 4 heteroatoms and/or 1 to 4 functional groups. Forcertain of these embodiments, Q contains one functional group. Forcertain of these embodiments, Q is preferably —C(O)N(R)(CH₂)₂—,—OC(O)N(R)(CH₂)₂—, —CH₂O(CH₂)₂—, or —CH₂—OC(O)N(R)—(CH₂)₂—, wherein R ishydrogen or C₁₋₄ alkyl.

For certain embodiments, including any one of the above embodiments,where R is present R is hydrogen.

The hydrolyzable groups, Y, of Formula Ia may be the same or differentand are capable of hydrolyzing, for example, in the presence of water,optionally under acidic or basic conditions, producing groups capable ofundergoing a condensation reaction, for example silanol groups.

Desirably, each Y of Formula Ia is independently a group selected fromthe group consisting of hydrogen, halogen, alkoxy, acyloxy, aryloxy, andpolyalkyleneoxy, more desirably each Y is independently a group selectedfrom the group consisting of alkoxy, acyloxy, aryloxy, andpolyalkyleneoxy, even more desirably each Y is independently a groupselected from the group consisting of alkoxy, acyloxy and aryloxy, andmost desirably each Y is independently an alkoxy group.

For certain embodiments, including any relevant embodiment describedherein:

-   -   Favorably alkoxy is —OR′, and acyloxy is —OC(O)R′, wherein each        R′ is independently a lower alkyl group, optionally substituted        by one or more halogen atoms. For certain embodiments, R′ is        preferably C₁₋₆ alkyl and more preferably C₁₋₄ alkyl. R′ can be        a linear or branched alkyl group.    -   Favorably aryloxy is —OR″ wherein R″ is aryl optionally        substituted by one or more substituents independently selected        from halogen atoms and C₁₋₄ alkyl optionally substituted by one        or more halogen atoms. For certain embodiments, R″ is preferably        unsubstituted or substituted C₆₋₁₂ aryl and more preferably        unsubstituted or substituted C₆₋₁₀ aryl.    -   Favorably polyalkyleneoxy is —O—(CHR⁴—CH₂O)_(q)—R³ wherein R³ is        C₁₋₄ alkyl, R⁴ is hydrogen or methyl, with at least 70% of R⁴        being hydrogen, and q is 1 to 40, preferably 2 to 10.

For certain embodiments, including any one of the above embodiments, xis 0.

For certain embodiments, including any one of the above embodimentsincluding a compound in accordance with Formula Ia, R_(f) is—CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂— and Q-C(R)₂—Si(Y)_(3-x)(R^(1a))_(x) isC(O)NH(CH₂)₃Si(OR′)₃ wherein R′ is methyl or ethyl. For certainembodiments, including any one of the above embodiments including anentity in accordance with Formula Ib, R_(f) is—CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂— and Q-C(R)₂—Si(O—)_(3-x)(R^(1a))_(x) isC(O)NH(CH₂)₃Si(O—)₃. For certain of these embodiments, m and p are eachabout 9 to 12.

The compounds of Formula Ia described above can be synthesized usingstandard techniques. For example, commercially available or readilysynthesized perfluoropolyether esters (or functional derivativesthereof) can be combined with a functionalized alkoxysilane, such as a3-aminopropylalkoxysilane, according to U.S. Pat. No. 3,810,874 (Mitschet al.).

For certain embodiments, the weight average molecular weight of thepolyfluoropolyether segment is about 1000 or higher, more desirablyabout 1800 or higher. Higher weight average molecular weights furtherfacilitate durability as well as minimizing a potential ofbioaccumulation. Generally for ease in use and application, the weightaverage molecular weight of the polyfluoropolyether segment is desirablyabout 6000 at most and more desirably about 4000 at most.

Polyfluoropolyether silanes, as indicated above, typically include adistribution of oligomers and/or polymers. Desirably for facilitation ofstructural integrity of polyfluoropolyether-containing coating as wellas minimization of a potential of bioaccumulation the amount ofpolyfluoropolyether silane (in such a distribution) having apolyfluoropolyether segment having a weight average molecular weightless than 750 is not more than 10% by weight (more desirably not morethan 5% by weight, and even more desirably not more 1% by weight andmost desirable 0%) of total amount of polyfluoropolyether silane in saiddistribution.

For certain embodiments, including any one of the above embodiments, thecomposition comprising an at least partially fluorinated compoundcomprising at least one functional group further includes an organicsolvent.

For certain embodiments, including any one of the above embodimentswherein the at least partially fluorinated compound comprising at leastone functional group is a polyfluoropolyether silane, thepolyfluoropolyether silane is desirably applied as a compositioncomprising the polyfluoropolyether silane and an organic solvent. Theorganic solvent or blend of organic solvents used typically is capableof dissolving at least about 0.01 percent by weight of thepolyfluoropolyether silane, in particular one or more silanes of theFormula Ia. It is desirable that the solvent or mixture of solvents havea solubility for water of at least about 0.1 percent by weight, and forcertain of these embodiments, a solubility for acid of at least about0.01 percent by weight.

Suitable organic solvents, or mixtures of solvents can be selected fromaliphatic alcohols, such as methanol, ethanol, and isopropanol; ketonessuch as acetone and methyl ethyl ketone; esters such as ethyl acetateand methyl formate; ethers such as diethyl ether, diisopropyl ether,methyl t-butyl ether and dipropyleneglycol monomethylether (DPM);hydrocarbon solvents such as alkanes, for example, heptane, decane, andparaffinic solvents; fluorinated hydrocarbons such as perfluorohexaneand perfluorooctane; partially fluorinated hydrocarbons, such aspentafluorobutane; hydrofluoroethers such as methyl perfluorobutyl etherand ethyl perfluorobutyl ether. For certain embodiments, including anyone of the above embodiments, the organic solvent is a fluorinatedsolvent, which includes fluorinated hydrocarbons, partially fluorinatedhydrocarbons, and hydrofluoroethers. For certain of these embodiments,the fluorinated solvent is a hydrofluoroether. For certain of theseembodiments, the hydrofluoroether is methyl perfluorobutyl ether. Forcertain embodiments, including any one of the above embodiments exceptwhere the organic solvent is a fluorinated solvent, the organic solventis a lower alcohol. For certain of these embodiments, the lower alcoholis selected from the group consisting of methanol, ethanol, isopropanol,and mixtures thereof. For certain of these embodiments, the loweralcohol is ethanol.

For certain embodiments, including any one of the above embodimentswhere the organic solvent is a lower alcohol and the compositioncomprises an at least partially fluorinated compound comprising at leastone silane group, the composition favorably further comprises an acid.For certain of these embodiments, the acid is selected from the groupconsisting of acetic acid, citric acid, formic acid, triflic acid,perfluorobutyric acid, sulfuric acid, and hydrochloric acid. For certainof these embodiments, the acid is hydrochloric acid.

The composition comprising an at least partially fluorinated compoundcomprising at least one functional group may favorably further comprisea non-fluorinated cross-linking agent that is capable of engaging in across-linking reaction. Preferably such a cross-linking agent comprisesone or more non-fluorinated compounds, each compound having at least twohydrolysable groups. Advantageously such a cross-linking agent comprisesone or more non-fluorinated compounds of silicon having at least twohydrolysable groups per molecule. Preferably the hydrolysable groups aredirectly bonded to the silicon in accordance to Formula II:

Si(Y²)_(4-g)(R⁵)_(g)  II

-   -   where R⁵ represents a non-hydrolysable group;    -   Y² represents a hydrolysable group; and    -   g is 0, 1 or 2.

The non-hydrolysable group R⁵ is generally not capable of hydrolyzingunder the conditions used during application of the compositioncomprising the at least partially compound comprising at least onefunctional group. For example, the non-hydrolysable group R⁵ may beindependently selected from a hydrocarbon group. If g is 2, thenon-hydrolysable groups may the same or different. Preferably g is 0 or1, more preferably g is 0. The hydrolysable groups Y² may be the same ordifferent and are generally capable of hydrolyzing under appropriateconditions, for example under acidic or basic aqueous conditions, suchthat the cross-linking agent can undergo condensation reactions.Preferably, the hydrolysable groups upon hydrolysis yield groups, suchas silanol groups capable of undergoing condensation reactions. Typicaland preferred examples of hydrolysable groups include those as describedwith respect to Formula Ia. Preferably, Y² is an alkoxy, —OR⁶, morepreferably an alkoxy where R⁶ is a C₁₋₄ alkyl.

Representative examples of favorable non-fluorinated silicon compoundsfor use in a cross-linking agent include tetramethoxysilane,tetraethoxysilane, tetrapropoxysilane, tetrabutoxysilane, methyltriethoxysilane, dimethyldiethoxysilane, octadecyltriethoxy-silane,3-glycidoxypropyltriethoxysilane, 3-aminopropyltrimethoxysilane,3-aminopropyl-triethoxysilane, 3-trimethoxysilylpropylmethacrylate andmixtures thereof. Preferably the cross-linking agent comprises C₁-C₄tetra-alkoxy derivatives of silicon, more preferably the cross-linkingagent comprises tetraethoxysilane.

The amounts by weight of the at least partially fluorinated compound tothe non-fluorinated cross-linking agent can change from about 10:1 toabout 1:100, preferably from about 1:1 to about 1:50 and most preferablyfrom about 1:2 to about 1:20.

For certain embodiments, e.g. compositions including a hydrolysablegroup, the composition may further comprise water.

The composition comprising an at least partially fluorinated compoundcomprising at least one functional group (in particular one silanegroup), including any one of the above embodiments, can be applied to atleast a portion of the surface of the non-metal coating using a varietyof coating methods. Such methods include but are not limited tospraying, dipping, spin coating, rolling, brushing, spreading and flowcoating. Preferred methods for application include spraying and dipping.For certain embodiments, including any one of the above embodiments, thecomposition comprising an at least partially fluorinated compoundcomprising at least one functional group, in any one of its abovedescribed embodiments, is applied by dipping at least a portion of thesubstrate upon which the non-metal coating has been formed in saidcomposition. Alternatively, for certain embodiments, including any oneof the above embodiments, the composition comprising the at leastpartially fluorinated compound comprising at least one functional group,including any one of its above described embodiments, is applied byspraying at least a portion of the substrate upon which the non-metalcoating has been formed with said composition.

In preferred embodiments where the composition comprises an at leastpartially fluorinated compound comprising at least one silane group (inparticular a polyfluoropolyether silane or more particularly any one ofthe embodiments of Formula Ia) and the non-metal coating comprisessilicon, oxygen, and hydrogen, for example, with —SiOH groups, uponapplication of said composition a extremely durable coating is formedthrough the formation of covalent bonds, including bonds in Si—O—Sigroups. For the preparation of such a durable coating, sufficient watershould be present to cause hydrolysis of the hydrolyzable groupsdescribed above so that condensation to form Si—O—Si groups takes place,and thereby curing takes place. The water can be present either in thetreating composition or adsorbed to the substrate surface, for example.Typically, sufficient water is present for the preparation of a durablecoating if the application is carried out at room temperature in anatmosphere containing water, for example, an atmosphere having arelative humidity of about 30% to about 80%.

Application is typically carried out by contacting the substrate withthe treating composition, generally at room temperature (typically about20° C. to about 25° C.). Alternatively treating composition can beapplied to a substrate that is pre-heated at a temperature of forexample between 60° C. and 150° C. Following application the treatedsubstrate can be dried and cured at ambient temperature or (preferably)at elevated temperatures (e.g. at 40° C. to 300° C.), and for a timesufficient to dry and cure. If desired or needed, the treatingcomposition may further comprise a thermal initiator. Alternatively orin addition thereto, following application of the treating compositionthe treated substrate may be cured (again if desired or needed) byirradiation (e.g. means of UV-irradiators, etc.). Hereto the treatingcomposition typically further comprises a photo-initiator, and curing isperformed in a manner known per se, depending on the type and presence,respectively of the photo-initiator used in the treating composition.

A post-treatment process may include a rinsing step (e.g. before orafter drying/curing, as desired or needed) to remove excess material,followed by a drying step.

Favorably the thickness of the fluorine-containing coating is at leastabout 20 nm, preferably at least about 30 nm, and most preferably atleast about 50 nm. For certain of these embodiments, the thickness is atmost about 300 nm, preferably at most about 200 nm, more preferably atmost about 150 nm, and most preferably at most about 100 nm.

For embodiments described herein including a non-metal coating and afluorine-containing coating, the combined thickness of the two coats maybe in the range of about 25 to about 5200 nm. Within this range,favorably the combined thickness of the two coats is less than about1000 nm, more favorably at most about 950 nm, even more favorably atmost about 850 nm, yet even more favorably about 750 nm and mostfavorably at most about 650 nm.

Additional aspects of the present invention include: devices andcomponents made in accordance with aforesaid methods; a medicinalinhalation device or a component of a medicinal inhalation devicecomprising a non-metal coating on at least a portion of a surface of thedevice or the component, as applicable, and a fluorine-containingcoating bonded to the non-metal coating wherein the fluorine-containingcoating comprises a composition comprising an at least partiallyfluorinated compound comprising at least functional one group whichshares at least one covalent bond with the non-metal coating.

Favorably the fluorine-containing coating is covalently bonded to thenon-metal coating through a plurality of covalent bonds, more favorablythrough covalent bonds including bonds in O—Si groups, more desirablyincluding bonds in Si—O—Si groups. Favorably the non-metal coating(covalently bonded to the fluorine-containing coating) comprises siliconand oxygen, more favorably carbon, silicon and oxygen. Depending on theparticular composition of the non-metal coating prior to application ofthe composition comprising an at least partially fluorinated compoundcomprising at least one functional group, after application of saidcomposition, the non-metal coating (covalently bonded to thefluorine-containing coating) may or may not comprise hydrogen. Generallyhowever, the non-metal coating (covalently bonded to thefluorine-containing coating) further comprises hydrogen. Desirably thenon-metal coating is substantially free of fluorine, more favorably freeof fluorine. Desirably the non-metal coating is substantially free ofnitrogen, more favorably free of nitrogen. Desirably the non-metalcoating is substantially free of sulfur, more favorably free of sulfur.Desirably the non-metal coating is covalently bonded to the at least aportion of a surface of the device or component, as applicable.Desirably the non-metal coating is a plasma deposited coating, and moredesirably a plasma deposited coating deposited under ion bombardmentconditions. Desirably the non-metal coating is a diamond-like glasscoating. Favorably the functional group of the at least partiallyfluorinated compound is a silane group. Favorably the at least partiallyfluorinated compound includes a polyfluoropolyether segment, morefavorably a perfluorinated polyfluoropolyether segment. Desirably the atleast partially fluorinated compound comprising at least one functionalgroup is polyfluoropolyether silane, more desirably a multifunctionalpolyfluoropolymer silane, and most desirably a difunctionalpolyfluoropolyether silane. Desirably in such polyfluoropolyethersilanes, the polyfluoropolyether segment(s) is (are) linked to thesilane segment(s) via a carbon-silicon functionality.

Further aspects of the present invention include: a medicinal inhalationdevice or a component of a medicinal inhalation device comprising anon-metal coating plasma deposited on at least a portion of a surface ofthe device or component, respectively, said coating being plasmadeposited under ion bombardment conditions and being substantially free(or more favorably) free of fluorine. Desirably the non-metal coating iscovalently bonded to the at least a portion of a surface of the deviceor the component, respectively. Favorably the non-metal coatingcomprises silicon, oxygen and hydrogen, more favorably carbon, silicon,oxygen and hydrogen. For these embodiments, it is favorable that thesilicon to oxygen ratio in the non-metal coating is less than two.

Other aspects of the present invention include: a medicinal inhalationdevice or a component of a medicinal inhalation device comprising adiamond-like glass coating (as described in detail above) on at least aportion of a surface of the device or component, respectively.

Besides the provision of medicinal inhalation devices and componentsthereof having desirable surface properties and structural integrity,methods of providing such medicinal inhalation devices and components asdescribed herein are advantageous in their versatility and/or broadapplicability to making various components of such medicinal inhalationdevices, such components having significantly differing shapes and formsmade of significantly differing materials. For example methods describedherein can be advantageously used to provide a coating on at least aportion of the interior surface (preferably on the entire interiorsurface, more preferably the entire surface) of an MDI aerosolcontainer, in particular a conventional MDI aerosol container made ofaluminum or an aluminum alloy as well as MDI aerosol containers made ofother metals, such as stainless steel. Methods described herein can alsobe advantageously used to provide a coating on at least a portion of asurface (preferably the entire) surface of a valve stem or a valve body,in particular a valve stem or a valve body made of a polymer such as PBTor acetal. In fact the same method (chemicals, process conditions, etc.)with little or no modification can used to coat aluminum or aluminumalloy MDI containers and metal and/or polymeric valve stems and valvebodies (typically stainless steel and/or PBT and/or acetal) as well ascompression springs (typically made of stainless steel) and actuators(typically made of polyethylene or polypropylene). This is particularadvantageous for large scale manufacturing and coating as well asstream-lining of manufacturing processing, facilities and/or equipmentfor coating, while at the same time allowing freedom in regard to theselection of the base material of a component and in some instancesexpanding the possibilities of the base material for a component.

As detailed above, particular embodiments (in particular thoseembodiments including a diamond-like glass coating either alone orover-coated with a fluorine-containing coating as described herein) havevery favorable impermeability characteristics. These coatings areparticular advantageous for use with DPI powder containers or MDIaerosol containers. Moreover due to their very favorable impermeabilitycharacteristics, such coatings allow the use of containers, e.g. MDIaerosol containers, made of plastic or other materials which in the pasthave been ruled out due to the potential of permeation of moisture fromoutside to the inside, permeation of aerosol formulation through or intothe container material and/or extraction of container material into theaerosol formulation. Furthermore, such coatings described herein thatare transparent or translucent can be used to provide a transparent ortranslucent plastic MDI aerosol container which can be advantageous inthat a patient can easily monitor the content of the container (i.e.whether it is empty and needs to be replaced).

Methods described herein can also be used to provide other medicinalinhalation devices including nebulizers, pump spray devices, nasalpumps, non-pressurized actuators or components of such devices.Accordingly medicinal inhalation devices or components described hereinmay also be nebulizers, pump spray devices, nasal pumps, non-pressurizedactuators or components of such devices.

Methods described herein can also be used to provide other componentsused in medicinal inhalation such as breath-actuating devices,breath-coordinating devices, spacers, dose counters, or individualcomponents of such devices, spacers and counters, respectively.Accordingly components described herein may also be breath-actuatingdevices, breath-coordinating devices, spacers, dose counters, orindividual components of such devices, spacers, counters, respectively.In regard to provision of a component or components of dose counters ofmedicinal inhalation devices, due to desirable surface properties andstructural integrity (in particular durability and resistance to wear)of coatings described herein, the provision of such a coating on acomponent or components (in particular movable component(s) and/orcomponent(s) in contact with a movable component) of a dose counterprovides dry lubricity facilitating smooth operation of the dosecounter.

Objects and advantages of this invention are further illustrated by thefollowing examples, but the particular materials and amounts thereofrecited in these examples, as well as other conditions and details,should not be construed to unduly limit this invention.

EXAMPLES Preparation of(CH₃O)₃Si(CH₂)₃N(H)C(O)CF₂O(CF₂CF₂O)₉₋₁₀(CF₂O)₉₋₁₀CF₂C(O)N(H)(CH₂)₃Si(OCH₃)₃

CH₃OC(O)CF₂O(CF₂CF₂O)₉₋₁₀(CF₂O)₉₋₁₀CF₂C(O)OCH₃ (a perfluoropolyetherdiester obtained from Solvay Solexis, Houston, Tex., available under thetrade designation “FOMBLIN ZDEAL”) (50 grams (g)) was added to anoven-dried 100-mL round bottom flask under a nitrogen atmosphere andstirred rapidly at room temperature using a magnetic stirrer.3-Aminopropyltrimethoxysilane (9.1 g) (obtained from GE Silicones,Wilton, Conn., available under the trade designation “SILQUEST A-1110”)was added to the flask in one portion. Initially the mixture wastwo-phase, and as the reagents mixed the mixture became cloudy. Areaction exotherm to a temperature of about 50° C. was observed, thereaction was continued for 2 hours at 60° C. and then the reactiongradually cooled to room temperature and became a slightly hazy lightyellow liquid. The reaction was monitored by gas chromatography (GC) toobserve excess 3-aminopropyltrimethoxysilane and Fourier transforminfrared spectroscopy (FTIR) to observe unreacted ester functionalgroups and was found to be complete within 90 minutes after the additionof the 3-aminopropyltrimethoxysilane.

The reaction product was stirred rapidly, and the pressure in the flaskwas reduced to 1 mmHg (133 Pa) gradually to minimize bumping. Methanolby-product was distilled from the flask over a period of two hours, and57.5 g of(CH₃O)₃Si(CH₂)₃N(H)C(O)CF₂O(CF₂CF₂O)₉₋₁₀(CF₂O)₉₋₁₀CF₂C(O)N(H)(CH₂)₃Si(OCH₃)₃was recovered from the flask. (Average molecular weight is about 2400and fraction of silane with a polyfluoropolyether segment having aweight average MW lower than 750 is zero).

Unless specified otherwise, plasma treatment followed by silanetreatment as described in the following were performed in the Examples.

Plasma Treatment Method

Exemplary components/substrates were treated in batch plasma systemPlasmatherm Model 3032, available from Plasmatherm, Kresson, N.J., whichwas configured for reactive ion etching with a 26-inch lower RF-poweredelectrode insulated from the chamber by a PTFE support and central gaspumping. The grounded chamber was connected to a roots style blower(Edwards Model EH1200, Boc Edwards, West Sussex, United Kingdom) backedby a dry mechanical pump (Edwards Model iQDP80, Boc Edwards). Plasma waspowered by a 5 kW, 13.56 MHz solid-state generator (RF Plasma ProductsModel RF50S0, available from MKS Power Generators and Subsystems,Wilmington, Mass.) and a radio frequency impedance matching network(Plasmatherm Model AMN-30, available from Plasmatherm). The system had anominal base pressure of 5 mTorr (0.67 Pa). The flow rates of gases werecontrolled by flow controllers available from MKS Power Generators andSubsystems. Components/substrates for deposition were placed on thelower powered electrode (and thus were located with the ion sheathformed upon plasma generation).

The plasma treatment included the following steps:

Step 1. Exemplary components/substrates were first treated in an oxygenplasma by flowing oxygen gas (99.99%, UHP Grade, available from ScottSpecialty Gases, Plumsteadville, Pa.), at 500 standard cubic centimetersper minute (sccm) flow rate and maintaining the pressure at 52 millitorr(mtorr) (6.9 Pascals (Pa)) and plasma power of 1000 watts. The oxygenpriming step was carried out for 60 seconds.Step 2. Following the oxygen plasma priming, tetramethylsilane (99.9%,NMR Grade, available from Sigma-Aldrich Chemicals, St. Louis, Mo.) wasintroduced. Tetramethylsilane vapor was introduced into the chamber at aflow rate of 150 sccm while the oxygen flow was maintained at 500 sccm.The pressure was held at 64 mtorr (8.5 Pa), and plasma power was held at1000 watts. The treatment time was 60 seconds, deposition rate about 170nm/min.Step 3. The tetramethylsilane gas was then shut off and the oxygen gascontinued to run at a flow of 500 sccm. The pressure was maintained at52 mtorr (6.9 Pa), and plasma power delivered at 1000 watts. This finalstep of post-deposition oxygen plasma treatment lasted 60 seconds.

The power density used in each step was 0.27 watts/square cm.

Typically batches of up to 50 exemplary components/substrates wereplaced in a tray on the lower powered electrode and the aforesaidthree-step-treatment was conducted three times. Between treatments, thechamber was vented to atmosphere and the tray was removed, shaken (toredistribute the components/substrates and their position on the tray),and then re-placed onto the lower powered electrode.

Specimen Micro-hardness (H) and Elastic Modulus (E) of such depositedcoatings on silicon wafer substrates were determined using a MTS DCMNanoindenter supplied by MTS Nano Instruments, 701 Scarboro Road Suite100 Oak Ridge, Tenn. 37830. The coatings were tested probing the samplefrom the top surface. For all experiments a diamond Berkovich probe wasused. Spatial drift was held at a maximum of 0.01 nm/s maximum. Aconstant strain rate experiment was run at 0.05/s to command depths of100 nm and in some cases 200 nm, to establish a depth for which theresults would be effectively independent of the substrate—this depth was50 nm. The dynamic excitation frequency, 75 hz, and amplitude of theindenter, 1 nm, were held constant. Results are quoted for 10-15measurements taken at different positions on the sample.

Micro-hardness and Elastic Modulus of deposited coatings using the sametest method as described above were determined except that the coatingwas not deposited under conditions of ion bombardment. In one case thesubstrate was placed at a floating potential and positioned so that thesubstrate was outside the ion sheath, and in another case the system wasmodified to include a grounded electrode (instead of the chamber actingas the grounded electrode) and the substrate was placed on a groundedelectrode.

Microhardness determined for plasma-deposited coatings deposited underconditions of ion bombardment (i.e. substrate was positioned on poweredelectrode) was 2.5 GPa, compared with 0.7 GPa (floating potential) and0.2 GPa (grounded electrode).

Elastic Modulus determined for plasma-deposited coatings deposited underconditions of ion bombardment (i.e. where substrate was positioned onpowered electrode) was 17.5 GPa, compared with 9.2 GPa (floatingpotential) and 2.6 GPa (grounded electrode).

Silane Treatment Method

A solution (3 liters (L)) of 0.1%(CH₃O)₃Si(CH₂)₃N(H)C(O)CF₂(CF₂CF₂O)₉₋₁₀(CF₂O)₉₋₁₀CF₂C(O)N(H)(CH₂)₃Si(OCH₃)₃in HFE-7100 fluid (available from 3M Company, St. Paul, Minn. under thetrade designation “NOVEC HFE-7100”) was placed in a 4-L beaker at roomtemperature. The beaker was placed in a dip coater. Each exemplarycomponent/substrate, which had been plasma-treated according to themethod described above, was fixed vertically above the solution,introduced and submerged entirely into the solution and held in placefor at least five seconds. Exemplary component(s) was (were) withdrawnfrom the solution allowed to drain and then placed in an aluminum pan.The pan was then placed in an oven at 120° C. for 60 minutes. Exemplarycomponents were then allowed to stand at least 24 hours. Thickness ofcoatings provided through this silane treatment method typically rangedfrom about 20 to 100 nm.

Example 1

Stainless steel compression springs and stainless steel primary valvebodies for metered dose valves of the type marketed under the tradedesignation SPRAYMISER (3M Company, St. Paul, Minn., USA) having a 50mcl metering chamber were treated. Coated components were then builtinto valves. Also control valves were constructed using uncoated springsand primary valve bodies.

As a model substance for particulate drug, Brilliant blue food dye(commercially available from Warner Jenkinson Europe Ltd. OldmeadowRoad, King's Lynn, Norfolk, PE 30 4 LA, UK), micronized using a fluidenergy mill to give a majority of particles in the range of 1 to 3microns, was used.

In order to evaluate the properties of the exemplary valves includingcoated components in comparison to the control valves, valves (3exemplary valves and 3 control valves) were crimped onto cans containingthe following model formulation to provide six test units.

Formulation #1 mg/ml % w/w Micronized Brilliant Blue food dye 0.1320.0109 Sub-micron anhydrous Lactose* 2.64 0.2179 Oleic acid 0.06060.0050 Dehydrated ethanol 24.2285 2.0000 HFA 134a 1184.3653 97.7662*micronized lactose monohydrate obtained from DMV International Pharmaunder the trade designation Pharmatose 325M was processed using anAvestin C50 high pressure homogenizer to give a majority of particles inthe range of 0.2 to 1 micron.

Each test unit was primed using 5 actuations and then actuated 50 times.Subsequently the units were chilled down to −60° C. and the valvesdetached from the cans. The valves were carefully disassembled. Eachspring and primary valve body was washed with 10 ml deionized water toquantitatively collect any Brilliant Blue food dye deposit on saidcomponent, and the amount of dye collected was determined viaphotospectrometric determination of light absorbance at 629 nmwavelength. The results are summarized in the following table (Table 1).

TABLE 1 Compression spring: Primary valve body: mcg of brilliant bluemcg of brilliant blue Example 1 Unit A 1.5 3.4 Unit B 1.4 3.9 Unit C 2.53.7 Control Unit A 11.0 11.9 Unit B 7.6 7.8 Unit C 9.2 14.1

Example 2

Acetal valve stems and PBT primary valve bodies for valves of the typemarketed under the trade designation BK357 (Bespak plc, Bergen Way,Kings Lynn Norfolk PE 30 2JJ) having a 50 mcl metering chamber weretreated. Coated components were then built into valves. Valves withnon-coated valve stems and primary valve bodies served as controls.Valves (3 exemplary valves and 3 control valves) were crimped onto canscontaining the following model formulation to provide six test units.

Formulation #2 mg/ml % w/w Micronized Brilliant Blue 1.2 0.0091 fooddye, as described above Oleic acid 0.0606 0.0050 Dehydrated ethanol24.2285 2.0000 HFA 134a 1185.9373 97.8959

Each test unit was primed using 5 actuations and then actuated 89 times.Subsequently, using a JJ Lloyd tensile tester, the valve force profile(force required to actuate and force applied by the valve stem on thevalve return stroke) of each of the unit was measured (3 repeats; 3actuations), and then the friction between the valve stem and seals(i.e. the valve friction) computed. The determined mean values for valvefrictions are given in Table 2. The determined return forces for themetering valves with treated components were in the range of 6.4 to 9.7Newtons. After force measurements, the units were chilled down to −60°C. and the valves detached from the cans. The valves were carefullydisassembled, and deposition on each valve stem and primary valve bodywas determined as described in Example 1, the results are summarized inTable 2.

TABLE 2 Valve friction Valve Stem: Primary Valve body: Newtons mcg ofbrilliant blue mcg of brilliant blue Example 2 Unit A 7.5 11 34 Unit B7.2 8 16 Unit C 9.0 14 21 Control Unit A 9.9 49 83 Unit B 10.6 31 125Unit C 10.2 38 73

Example 3

Compression springs, primary valve bodies and machined valve stems, allmade of stainless steel for metered dose valves of the type similar tothat shown in FIG. 1 having a 63 mcl metering chamber were treated.Treated components were then built into valves. Also control valves wereconstructed in the conventional manner using untreated compressionsprings, primary valve bodies and machined valve stems. Valves (5exemplary valves and 5 control valves) were crimped onto cans containinga formulation consisting of 1.97 mg/ml albuterol sulfate (having amajority of particles in the range of 1 to 3 microns) and HFA 134a toprovide ten test units. Each test unit was primed using 5 actuations andthen actuated 200 times. Subsequently, the valve force profile (forcerequired to actuate and force applied by the valve stem on the valvereturn stroke) of each of the unit was measured as described Example 2.Determined valve friction results are reported in Table 3, and returnforce for metered dose valves assembled with treated components wasfound to be in the range 5.8 to 11.6 Newtons. Similar to Example 2deposition measurements were carried out. Here, units were punctured toeject the remaining liquid contents, and the valves detached andcarefully disassembled. Each component to be assayed for drug was placedin a lidded tube. 5 ml of sample diluent (45:55 Methanol:0.1% PhosphoricAcid Solution) was dispensed into each tube, replacing lids immediatelyafter dispensing the diluent. Each tube was then placed in a sonic bathfor 2 minutes then shaken gently by inversion and swirling for 1 minuteto collect quantitatively any albuterol sulfate deposit on saidcomponent. An aliquot from each tube was then transferred for analysisby HPLC to determine the amount of albuterol sulfate deposited. Theresults are summarized in Table 3.

TABLE 3 Valve Compression Valve Primary friction Spring: Stem: Valvebody: Newtons mcg of albuterol sulfate Example 3 Unit A 11.7 152.7 *156.5 Unit B 6.1 301.7 73.7 222.1 Unit C 13.2 243.4 90.5 171.5 Unit D12.2 144.3 69.6 115.5 Unit E 9.8 243.7 85.0 255.9 Control Unit A 18.81252.1 616.4 515.0 Unit B 18.0 1636.0 611.3 492.1 Unit C 16.9 1064.5419.0 404.9 Unit D 18.5 1140.3 604.7 388.0 Unit E 17.1 1233.3 547.0342.8 * not measured due to contamination of sample

Example 4

In this example, exemplary components/substrates were treated with thefollowing Tumbling Plasma Treatment Method to provide components withjust a diamond-like-glass coating.

Tumbling Plasma Treatment Method

Exemplary components/substrates were treated in a custom-built, tumblingcylindrical plasma system. The chamber is a quartz tube (with fourinternal baffles) which is 15 cm in diameter and 30 cm long, to whichaluminum end flanges are attached by means of a vacuum grade sealant(Ton-Seal). Each of the end-flanges is provided with a 1.5 inch diameterstainless tube, where one is connected via a rotary seal to roots styleblower (Alcatel Model RSV600, Annecy, France) backed by a mechanicalpump (Leybold Model D65BCS, Export, Pa., USA), and the other connectedvia a rotary seal to a gas supply system. Plasma was generated by a 6 mmthick copper external electrode, 15 cm wide and 25 cm long, locatedbelow the quartz tube whose axis is horizontal. The copper electrode wasrolled into an arc of a circle so that the 15 cm width of the electrodewas conformed to the curvature of the quartz tube but separated from thetube by a gap of 2 mm. The entire quartz tube assembly was housed insidea housing constructed from perforated sheet metal which served to act asthe grounded counter electrode and also the Faraday shield, preventingthe electromagnetic radiation from escaping into free space surroundingthe plasma system. The smaller powered electrode located within a muchlarger perforated metal ground structure constituted an asymmetricplasma system. Plasma was powered by a 1 kW, 13.56 MHz solid-stategenerator (Seren, Model No. R1001, available from Seren IPS, Inc.,Vineland, N.J., USA) and a radio frequency impedance matching network(Rf Plasma Products Model AMN-10, available from Advanced Energy, FortCollins, Colo.). The system had a nominal base pressure of 5 mTorr (0.67Pa). The flow rates of gases were controlled by flow controllersavailable from MKS Power Generators and Subsystems, Wilmington, Mass.Components/substrates for deposition were placed inside the quartz tubeand were essentially located within the ion sheath adjacent to thepowered electrode, said powered electrode being located just underneaththe quartz tube. The quartz tube was rotated constantly at a slow speedof 1.2 revolutions per minute.

The plasma treatment included the following steps, each step using apower density of 0.53 watts/square cm:

Step 1. Exemplary components/substrates were first treated in an oxygenplasma by flowing oxygen gas (99.99%, UHP Grade, available from ScottSpecialty Gases, Plumsteadville, Pa.), at 100 standard cubic centimetersper minute (sccm) flow rate and maintaining the pressure at 120millitorr (mtorr) (15.9 Pascals (Pa)) and plasma power of 200 watts. Theoxygen priming step was carried out for 300 seconds.Step 2. Following the oxygen plasma priming, tetramethylsilane (99.9%,NMR Grade, available from Sigma-Aldrich Chemicals, St. Louis, Mo.) wasintroduced. Tetramethylsilane vapor was introduced into the chamber at aflow rate of 60 sccm while the oxygen flow was maintained at 30 sccm.The pressure was held at 100-150 mtorr (13-20 Pa), and plasma power washeld at 200 watts. The treatment time was 900 seconds.

(A post-treatment with oxygen plasma was not performed in order to leavethe deposited diamond-like-glass film in its native, deposited surfacecondition.)

Typically batches of up to 500 exemplary components/substrates wereplaced inside the quartz tube and the tube rotated at 1.2 revolutionsper minute while the plasma treatment steps 1 and 2 were being done.Between deposition runs, deposition build-up on the quartz wall wascleaned off by using an abrasive pad followed by vacuuming of theresulting dust; said cleaning was done in order to prevent any potentialof material/build-up from previous run(s) on the quartz wall flaking offduring deposition, getting incorporated into the growing thin film andcausing defects in said growing film. After the deposition of the filmthe quartz tube chamber was vented to atmosphere and the componentstaken out.

Compression springs, primary valve bodies and machined valve stems ofthe type used in Example 3 were treated using the aforesaid TumblingPlasma Treatment Method. Treated components were then built into valves,and the valves (5 exemplary valves) were crimped onto cans containing analbuterol sulfate formulation of the type used in Example 3, wherealbuterol-sulfate-deposition measurements were carried out as describedin Example 3. The results are summarized in Table 4.

TABLE 4 Compression Valve Primary Spring: Stem: Valve body: Example 4mcg of albuterol sulfate Unit A 190.7 107.1 113.4 Unit B 134.6 92.9165.1 Unit C 180.1 109.6 178.2 Unit D 171.8 94.8 162.8 Unit E 125.2106.5 64.2

1.-24. (canceled)
 25. A method of making a medicinal inhalation deviceor a component of a medicinal inhalation device comprising: a) forming anon-metal coating on at least a portion of a surface of the device orthe component, respectively, said coating having at least one functionalgroup; b) applying to at least a portion of a surface of the non-metalcoating a composition comprising an at least partially fluorinatedcompound comprising at least one functional group; and c) allowing atleast one functional group of the at least partially fluorinatedcompound to react with at least one functional group of the non-metalcoating to form a covalent bond.
 26. A method according to claim 25,wherein said at least one functional group of the non-metal coating hasan active hydrogen.
 27. A method according to claim 25, wherein thenon-metal coating is formed by plasma deposition.
 28. A method accordingto claim 27, wherein the non-metal coating is formed by plasmadeposition under ion bombardment conditions.
 29. A method accordingclaim 25, wherein the non-metal coating comprises silicon, oxygen andhydrogen.
 30. A method according to claim 29, wherein the non-metalcoating further comprises carbon.
 31. A method according to claim 30,wherein the non-metal coating is a diamond-like glass containing on ahydrogen free basis at least about 20 atomic percent carbon and at leastabout 30 atomic percent of silicon+oxygen.
 32. A method according to anyone of claims 29, wherein the silicon to oxygen ratio in the non-metalcoating is less than two.
 33. A method according to claim 25, whereinsaid at least partially fluorinated compound is selected from: (i) acompound that comprises a hydrolysable group; (ii) a compound thatcomprises a silane group; (iii) a compound that comprises apolyfluoropolyether segment; and (iv) a compound that comprises apolyfluoropolyether silane.
 34. A method according to claim 33, whereinsaid at least partially fluorinated compound comprises apolyfluoropolyether segment, wherein the polyfluoropolyether segment hasweight average molecular weight of about 1000 or higher and/or is aperfluorinated polyfluoropolyether segment, wherein the repeating unitsof the perfluorinated polyfluoropolyether segment the number of carbonatoms in sequence is at most
 6. 35. A medicinal inhalation device or acomponent of a medicinal inhalation device comprising a non-metalcoating on at least a portion of a surface of the device or thecomponent, respectively, and a fluorine-containing coating bonded to thenon-metal coating wherein the fluorine-containing coating comprises anat least partially fluorinated compound comprising at least onefunctional group which shares at least one covalent bond with thenon-metal coating.
 36. A device or a component according to claim 35,wherein the fluorine-containing coating is covalently bonded to thenon-metal coating through a plurality of covalent bonds, in particular aplurality of covalent bonds including bonds in O—Si groups, moreparticularly bonds in Si—O—Si groups.
 37. A medicinal inhalation deviceor a component of a medicinal inhalation device comprising a non-metalcoating plasma deposited on at least a portion of a surface of thedevice or the component, respectively, said coating being plasmadeposited under ion bombardment conditions and being substantially freeof fluorine, in particular free of fluorine.
 38. A medicinal inhalationdevice or a component of a medicinal inhalation device comprising adiamond-like glass coating on at least a portion of a surface of thedevice or the component, respectively.